Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].Cl.N[C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1.[BrH:22]>O.[Cu]Br>[Br:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)[nH]c(=O)n1c(=O)[nH]nc21
Agent: [Cu]Br
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=c1[nH]nc2c3ccc(Br)cc3[nH]c(=O)n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
63.8 mg (0.92 mmol) of sodium nitrite were added at 0° C. to a suspension of 210 mg (0.83 mmol) of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione hydrochloride in 5 ml of 48% hydrobromic acid. The mixture was stirred at 0° C. for 1 hr. and then 132 mg (0.99 mmol) of copper(I) bromide in 2 ml of water were added dropwise. After stirring at RT for 16 hrs. the precipitate was filtered off, washed with methanol and dried in a vacuum. 57 mg (24%) of 8-bromo-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were obtained as yellowish crystals;
Reaction SMILES: OS(O)(=O)=O.C([O-])=O.[CH3:9][C:10]12[CH:17]([OH:18])[C:14]([CH3:19])([CH2:15][CH2:16]1)[CH2:13][CH2:12][CH2:11]2>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:19][C:14]12[C:17](=[O:18])[C:10]([CH3:9])([CH2:16][CH2:15]1)[CH2:11][CH2:12][CH2:13]2
Reactant: CC12CCCC(C)(CC1)C2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC12CCCC(C)(CC1)C2=O
Temperature: 0 °C

Procedure:
A quantity of 56 ml of 98% H2SO4 was added dropwise with stirring and cooling to a solution of 67 g of CrO3 (0.67 mol) in 100 ml of ice water. The mixture was diluted with water to a total volume of 200 ml. The solution obtained was added with stirring to a solution of 54.6 g (0.32 mol) of the formate of 1,5-dimethylbicyclo [3,2,1] octan-8-ol and 0.5 g of tetrabutylammonium chloride in 120 ml of acetone at such a rate that the temperature of the reaction mixture was 35°-40° C. The mixture was stirred for a further 2 hours at 35° C. and subsequently, the acetone solution was separated from the bottom layer. The latter was extracted a few times with acetone and the extracts were added to the acetone solution. The mixture was washed with a saturated K2CO3 solution and subsequently dried on K2CO3. The acetone was distilled off and the residue was vacuum-distilled. The distillate was dissolved in 100 ml of pentane and refluxed for 10 minutes after the addition of 50 ml of a 25% KOH solution in methanol. The pentane solution was washed with water and dried on Na2SO4. After the pentane had been distilled off, the residue was vacuum-distilled after the addition of 1 g of sodium. A quantity of 41 g of 1,5-dimethylbicyclo [3,2,1] octan-8-one was obtained having a boiling point of 104° C. at a pressure of 22 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(C)c2)c1C(=O)OC
Yield: 114.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.4 mmol) in acetone (30 mL) and potassium carbonate (2.7 g, 19.3 mmol) was added 1-bromomethyl-3-methyl-benzene (0.91 mL, 6.7 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-methyl-benzyloxy)-phthalic acid dimethyl ester (2.3 g, 115% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[N:22][CH:23]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O>CO>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@@H:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[N:22][CH:23]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(C(C)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Agent: O=C=O
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@H](C)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1

Procedure:
The racemic 5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (prepared as in Example 146) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 75% CO2: 25% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as a white foam with Tr of 14.89 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:24]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:24])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccccc3)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-7-methoxy-4-phenylamino-quinazolin-6-ol (0.16 g, 0.524 mmol) (from Example 15, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.62 mmol) and methyl iodide (0.15 g, 1.05 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:5:0.05) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine as a pale yellow solid. (Yield 0.13 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
4'-Hydroxyacetophenone (10 g, 73.4 mmole) was suspended in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen at 0° C. The suspension was treated with diisopropylethylamine (14.7 ml, 84.5 mmole) followed by acetyl chloride (6.0 ml, 84.5 mmole) in 1×50 ml dichloromethane slowly dropwise. The reaction mixture was stirred 30 minutes at 0° C. and then for 1 hour at room temperature. The mixture was washed with 1×100 ml 10% hydrochloric acid and the organics were dried over magnesium sulfate. The dried organics were concentrated in vacuo to a yellow oil. The oil was distilled via kugelrohr (high vacuum, 165° C.) to give 12.25 g (94%) of 4'-acetoxy-acetophenone as a white solid. Melting Point: 47°-49° C. 4'-Acetoxy-acetophenone (10 g, 56.2 mmole) was dissolved in acetic anhydride (10.6 ml, 112.2 mmole) in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C. and boron trilfuoride gas was bubbled into the reaction mixture until it was saturated. The reaction was stirred 1 hour at room temperature and was poured into 600 ml diethyl ether. The orange precipitate was collected, washed with fresh diethyl ether, and was dried to afford 6.6 g (43%) of a boron difluoride complex. Melting Point: 130°-132° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=2)[CH3:16])=[O:19])[CH:28]=[CH:29][CH:30]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2cccc(Cl)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(3-chloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28ClNO5 [M−H]−: 434.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:11]1[CH:16]([OH:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I>C1COCC1>[C:31]([O:30][C:28]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C@H:11]1[C@H:16]([O:17][CH3:35])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)CCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of NaH (1.3 equiv.) in THF (0.1M) was added benzyl 3-(bis(tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) and the reaction was heated to 50° C. for 10 min. Upon cooling to room temperature, MeI (1.5 equiv.) was added and the solution was allowed to stir for 16 h. The reaction was quenched with water, then extracted with EtOAc, the organic was dried with brine and Na2SO4, and concentrated. The crude material was purified via silica gel column chromatography eluting with EtOAc and hexanes (1:3) to give a clear oil in 71% yield. LCMS (m/z): 365.0 (MH+).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[N:19]=[N:20][CH:21]=[CH:22][CH:23]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[N:19]=1
Reactant: Nc1cccnn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1cnnc(N=C2SC[C@@H]3Cc4ccccc4CN23)c1
Yield: 65.7 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 3-aminopyridazine (9.5 g) as the starting materials, (S)-3-(pyridazin-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (9.3 g) is obtained in the form of light beige crystals, m.p.=140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][OH:19])=[NH:17])=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][O:19][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[NH:17])=[CH:12][N:11]3[CH:20]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)ONC(=N)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
2-(4-Fluoro-phenyl)-N-hydroxy-imidazo[1,2-a]pyridine-6-carboxamidine (example 56; 85.1 mg, 0.315 mmol) was dissolved in 5 ml DMF. The mixture was heated to 80° C. after addition of triethylamine (87.8 μl, 0.63 mmol) and ethyl chloroformate (33 μl, 0.34 mmol) for 2.5 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 48 mg (45%) of the desired product. MS: M+H+=343.05.
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[CH:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc([P+](Cc2ccc3ccccc3n2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 2-quinolylmethyltriphenylphosphonium chloride (8.72 g) was dissolved in anhydrous THF (60 ml), and a 1.6N solution (15 ml) of butyllithium was added dropwise over 20 minutes under cooling on ice. The mixture was then stirred for 10 minutes at room temperature. To the mixture, an anhydrous THF (24 ml) solution of 1-tert-butoxycarbonyl-4-ketopiperidine (4.29 g) was added dropwise over 15 minutes under cooling on ice. The mixture was stirred for 30 minutes under cooling on ice and further stirred overnight at room temperature. Water (200 ml) was added to the reaction mixture, then the resultant mixture was extracted with ether. The organic phase was back-extracted with 1N hydrochloric acid, and the aqueous phase was neutralized with a saturated solution of sodium hydrogencarbonate. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby obtain the title compound as a solid. This solid was used for subsequent reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N)c(NCCc2ccccc2)c1
Yield: 100 %

Procedure:
A mixture comprising 3-methoxy-4-nitrobenzonitrile (1 g, 5.6 mmol), phenethylamine hydrochloride (1.8 g, 11.2 mmol), 50% sodium hydroxide (0.9 g, 11.2 mmol) and DMSO (3 mL) was heated at 100° C. for 3.5 hours, cooled and poured into a solution of 1N hydrochloric acid (200 mL, 0° C.). The mixture was stirred for 20 minutes to give a precipitate. The precipitate was collected and recrystallized from hot ethanol to provide 4-nitro-3-phenethylaminobenzonitrile (0.78 g, 2.9 mmol) as orange crystals. MS (CI), Calculated for C15H13N3O2, 267.3, Found (MH+): 282. A mixture comprising 4-nitro-3-phenethylaminobenzonitrile (0.75 g, 2.8 mmol), palladium on carbon (100 mg) and 1:1 methanol/THF (100 mL) was hydrogenated under 1 atm for 3 hours, filtered and concentrated under reduced pressure to provide 4-amino-3-phenethylaminobenzonitrile (0.68 g, 2.8 mmol) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[S:44](Cl)(=[O:46])=[O:45])[CH:37]=[CH:36][CH:35]=1.O>ClCCl>[CH3:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([S:44]([C:42]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:43]=3[N:34]=[CH:35][CH:36]=[CH:37]4)(=[O:45])=[O:46])[C:13]2=[O:26])=[CH:20][CH:19]=1)([CH3:24])[C:22]#[N:23]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added quinoline-8-sulfonyl chloride (100 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 32 mg (20%); 1H NMR (DMSO-d6, 300 MHz): δ 9.468 (s, 1H), 8.700-8.729 (d, 1H, J=8.7 Hz), 8.539-8.558 (m, 2H), 8.449-8.479 (d, 1H, J=9 Hz), 7.974-8.004 (d, 1H, J=9 Hz), 7.864-7.916 (t, 1H), 7.716-7.744 (d, 2H, J=8.4 Hz), 7.519-7.600 (q, 1H), 7.470-7.491 (m, 3H), 6.435 (s, 1H), 2.118 (s, 3H), 1.743 (s, 6H); MS: m/z 534 (M+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[C:7]2[N:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:17]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CN(C(C)=O)c1ccc(N)cc1-2
Yield: 91 %

Procedure:
The product was obtained as the acetic acid salt from the material from step 1 (10 g, 0.0236 mol) and by the method of Example 17. 9.8 g. (FW=454.45, 91% yield). LC/MS m/z=395 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:11][CH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(F)cc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: N#Cc1cc(F)cc(CBr)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
3-Fluoro-5-methylbenzonitrile (Hognda Trading; 100 g, 0.74 mol) was taken in acetonitrile (1 L) at 25° C. under nitrogen atmosphere. N-Bromosuccinimide (105 g, 0.59 mol) and AIBN (2.4 g, 0.014 mol) were added and the reaction mixture was heated at 70° C. for 1 h 20 minutes. The reaction mixture was cooled to 25° C. and concentrated. The residue was diluted, cooled to 0-5° C. and stirred for 15 minutes at the same temperature. The precipitated succinimide was filtered and the filtrate was concentrated to get crude product as yellow oil (90 g). It was taken in petroleum ether (200 mL) and cooled to −20° C. stirred for 30 minutes. The precipitated solids were filtered and dried to get the title product as white solid. 1H NMR (DMSO-d6; 400 MHz): δ 7.83 (m, 2H), 7.73 (m, 1H), 4.72 (s, 2H). HPLC (Method A) Rt: 4.17 min (Purity: 99.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.Br.[NH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:16].C(N(CC)CC)C.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH:13][CH2:14][C:15]([NH:17][C:18]2[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=2[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of m-methoxyphenylisocyanate (734 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0°0 C. for 30 minutes and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and distilled under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6x (1.29 g, 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O)(=O)C.[OH-].[Na+]>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: C=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(CCc2ccncc2)CC1
Temperature: 160 °C
Yield: 86 %

Procedure:
In a tube, 2 ml (19 mM) of 4-vinylpyridine, 3.16 ml (28.5 mM) of N-methylpiperazine, and 200 μl of acetic acid are mixed in 12 ml of ethanol. The tube is closed and heated for 10 minutes at 160° C. in a microwave oven. After cooling, 20 ml of 0.5N sodium hydroxide are added slowly and the mixture is extracted with dichloromethane. The separated organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The product sought after is thus obtained as a yellow oil (yield=86%).
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[OH:28])([O:4]P(O)(O)=O)(=[O:3])[OH:2].[CH3:29]OP(OC)(OC)=O.P(Cl)(Cl)(Cl)=O>C(OCC)C>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[C@@H:12]1[O:28][CH3:29])([OH:4])([OH:2])=[O:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COP(=O)(OC)OC
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@@H]1COP(=O)(O)O

Procedure:
In a clean, dry 500 mL round bottom flask equipped with a stirring bar and under a stream of argon slowly add dry and finely powdered 3′-O-Me-Guanosine (1), (6 g, 20 mmol) to a mixture of trimethylphosphate ((OMe)3P) (50 mL) and phosphorous oxychloride (POCl3) (6 mL, 60 mmol) at 0° C. in small portions with continuous stirring under argon. The mixture was kept at 0-4° C. and allowed to stir at least 19 hrs. Diethyl ether (200 mL) was added to extract the excess phosphorous oxychloride and to simultaneously precipitate the 3′-O-methylguanosine-5′-phosphodichloridate, which was then pelleted by centrifugation and dissolved in 100 mL ice-cold 5% NaHCO3 in water. The resulting aqueous solution was adjusted to pH ˜1.5 using 1 N NaOH. After stirring at 0-4° C. for an additional 20 h, the pH was adjusted to 7.0 and the resulting mixture was applied to a column of DEAE Sephadex A25. The column was washed with 5 mM TEAB buffer, pH 7.5 and then eluted with freshly prepared 1M Triethylammonium bicarbonate (TEAB) buffer, pH 7.5. Fractions containing the 3′-O-Me GMP TEA salt (2) were pooled, concentrated to dryness.