Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:49])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:28])[CH2:15][S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:6][CH:7]=2)=[CH:36][CH:35]=1)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)CSCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzylsulfanyl)-ethanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[NH:23][C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32]([O:34][CH2:35]Cl)[CH3:33]>O1CCCC1.C(OCC)C>[C:26]1([CH2:25][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:20]3[N:21]=[C:22]([CH3:24])[N:23]([CH2:35][O:34][CH2:32][CH3:33])[C:19]=3[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOCCl
Reactant: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (0.064 g, 2 mmole) in tetrahydrofuran (15 mL) was cooled in an ice bath. N,N-bis(phenylmethyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.32 mmole) was added and the reaction mixture was allowed to warm to room temperature for 20 minutes. Chloromethyl ethyl ether was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with diethyl ether, washed twice with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methylene chloride) to provide 0.43 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[C:9]1([CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:22]([C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=2)=[CH:26][CH:25]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:9]1([CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:24]3[CH:39]=[CH:38][C:27]([O:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)=[CH:26][CH:25]=3)[CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(C2CCCCNC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCCC(c4ccccc4)C3)cc2)nc1
Yield: 92.4 %

Procedure:
Using a method similar to Example 345, using 3-phenyl-azepane fumaric acid salt (0.122 g, 0.419 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.129 g, 0.609 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.154 g (93%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2199; 1H NMR (DMSO-d6): 8.61 (d, 1H, J=1.8 Hz), 8.25 (dd, 1H, J=2.6, 8.8 Hz), 8.02 (s, 1H), 7.47 (s, 1H), 7.38 (d, 2H, J=8.4 Hz), 7.27-7.02 (m, 5H), 3.70 (d, 1H, J=13.5 Hz), 3.64 (d, 1H, J=13.5 Hz), 2.89-2.63 (m, 5H), 1.81-1.59 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])([O-:3])=[O:2].C(N=[C:20]=[O:21])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([N:14]=[C:20]=[O:21])(=[O:12])=[O:13])([O-:3])=[O:2]
Reactant: NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 9.0 g of the product of Example 3, 4.2 g of butyl isocyanate and 0.1 g of DABCO in 80 ml of dry xylenes was heated to 136°. To this solution was added 3.0 ml of liquid phosgene at such a rate as to maintain the temperature between 125° and 136°. This addition required about 21/2 hours. The solution was cooled to 25°, filtered under nitrogen and stripped in vacuo to give crude 2-nitrophenylmethanesulfonyl isocyanate as a viscous, moisture-sensitive oil showing a sulfonyl isocyanate peak in the infrared at 2230 cm-1.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:2].CCN(CC)CC.[SH2:20]>N1C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[S:20])[NH2:2]
Reactant: N#CCc1ccc(C(=O)O)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24 mmol) and Et3N (5 ml) in pyridine, H2S was bubbled during 3 h. The reaction mixture was stirred 16 h at room temperature. Water was then added to the reaction mixture which was agitated for 1 h before acidifying to pH 6 with 1M HCl. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 250 (2.08 g, 83%) as a white solid. 1H NMR (DMSO) δ (ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 3.88 (s, 2H).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([C:16]4[C:17]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)=[N:18][C:19]5[C:24]([N:25]=4)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=5)[C:14]=3[CH:15]=[C:6]2[O:5][CH2:4]1>CO.O>[O:3]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([C:16]4[C:17]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)=[N:18][C:19]5[C:24]([N:25]=4)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=5)[C:14]=3[CH:15]=[C:6]2[O:5][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Sodium hydroxide (35 mg, 0.88 mmol) was added to a solution of methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.22 mmol) in methanol (30 ml) and water (1.0 ml) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3 N) to give a precipitate which was collected by filtration to afford 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (70.0 mg, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH:17][S:36]([CH3:35])(=[O:38])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2.5 h

Procedure:
(S)-N6-Benzyloxycarbonyllysine (1.5 kg) was slurried in methylene chloride (7.5 l) and chlorotrimethylsilane (1.36 l) added over 10 minutes. The mixture was heated under reflux for 30 minutes to give a solution which was cooled to 3° C. before simultaneously adding diisopropylethylamine (1.87 l) and methanesulphonyl chloride (435 ml) at such a rate as to keep the temperature below 25° C. The reaction was stirred for a further 2.5 hours then poured into 2 M aqueous hydrochloric acid solution. The layers were separated and the methylene chloride phase was washed with 2 M aqueous hydrochloric acid solution followed by water. The solvent was removed under reduced pressure and replaced with n-butyl acetate. The solution was cooled and the resulting crystalline material was collected by filtration, washed with n-butyl acetate and dried under reduced pressure to provide the title compound (1.63 kg), m.p. 83.5-84° C. [α]D25−13.4° (c=1, methanol). Found: C,50.23; H,6.40; N,7.76.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][N:14]=1>>[CH3:11][O:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ccccc1C(=O)O
Product: COc1ccc(CNc2ccccc2C(=O)O)cn1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-methoxypyridine-5-carboxaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 169.9, 162.9, 150.4, 145.7, 138.6, 134.4, 131.7, 127.7, 114.7, 111.7, 110.5, 110.5, 53.1, 42.8.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[F:30][P-:31]([F:36])([F:35])([F:34])([F:33])[F:32].[K+]>O>[F:30][P-:31]([F:36])([F:35])([F:34])([F:33])[F:32].[CH2:15]([O:23][C:24]1[CH:25]=[CH:26][C:27]([S+:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:28][CH:29]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCOc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: CCCCCCCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 42 °C
Yield: 74 %

Procedure:
A mixture of 12.12 grams (0.06 mole) of diphenylsulfoxide, 10.3 gram of octylphenyl ether and 20 ml of PP/MSA resulted in an exothermic reaction. The temperature of the mixture increased to 42° C. After the exotherm had subsided, the temperature was raised to 50° C. and maintained at that temperature for 1 hour with stirring. There was obtained a complex reaction product of diphenylsulfoxide and octylphenyl ether. The mixture was then poured into 200 ml of water. A clear yellow solution was obtained. There was added to the solution, 9.5 grams of potassium hexafluorophosphate. A yellow oil precipitated from the solutionwhich solidified to a white crystalline solid upon standing. The mixture was warmed slightly to 40° C. and stirred. There was obtained a quantitative yield of crude product. The product was recovered by filtering and washed twice with water followed by petroleum ether. The crude product was further purified by recrystallization from absolute ethanol. (4-octyloxyphenyl)diphenylsulfonium hexafluorophosphate was obtained at a 74% yield. It had a melting point of 94°-95° C.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(N(CC)CC)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(CCCC(=O)C=Cc2ccc(OC3CCCCO3)c(OC3CCCCO3)c2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(CCCC(=O)C=Cc2ccc(O)c(O)c2)cc1OC
Reaction time: 1 h
Yield: 82 %

Procedure:
In 5 ml of absolute methanol was dissolved 100 mg of 1-(3,4-bistetrahydropyranyloxyphenyl)-6-(3,4-dimethoxyphenyl)-3-oxo-1-hexene obtained in Example 15-(1). A catalytic amount of p-toluenesulfonic acid was added to the solution at 0° C. and a stirring was effected at the same temperature for 1 hour. After the reaction, 1 drop of triethylamine was added to the reaction mixture and then the mixture was concentrated to give crude product. By purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=1:1), 55 mg of the above caption compound was obtained.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:32]([N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cccc2ccccc12)N1C(=O)N(Cc2ccccc2)C(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (200 mg) was dissolved in DMF (2 mL), benzyl bromide (45 mg) was added, and potassium carbonate (36 mg) was further added. The reaction solution was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was recrystallized from IPE to obtain 55 mg of white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[Cl:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:23][CH2:24]3)[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1
Reactant: CCOC(=O)NCCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 12.94 parts of ethyl (2-bromoethyl)carbamate, 15.68 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.08 parts of sodium hydrogen carbonate and 160 parts of ethanol is stirred and refluxed overnight. The formed precipitate is filtered off and washed with trichloromethane. The layers from the filtrate are separated. The organic phase is dried, filtered and evaporated. The residue is stirred in 2-propanone. The unreacted starting material is filtered off and the filtrate is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol 70%. The product is filtered off and dried, yielding 6.5 parts of ethyl {2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-ethyl}carbamate; mp. 187.7° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Cl)=[N:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:5]1[C:6]2[N:7]([CH:8]=[CH:9][N:10]=2)[C:2]([Cl:1])=[CH:3][N:4]=1)[CH3:13]
Reactant: CCN
Reactant: Clc1ncc(Cl)n2ccnc12
Product: CCNc1ncc(Cl)n2ccnc12
Reaction time: 12 h

Procedure:
A solution of 1.5 g (9.8 mmol) of 5,8-dichloroimidazo[ 1,2-a]pyrazine in 25 ml of a 40% strength aqueous ethylamine solution is maintained with stirring for 12 hours. After concentration under reduced pressure and chromatography on a silica column (eluant=ether), 5-chloro-8-ethylaminoimidazo[1,2-a]pyrazine (m.p. 94° C.), is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:16][CH2:17][CH3:18].[Na+].O>C(O)C>[CH2:17]([O:16][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:18]
Reactant: CCc1c(Cl)nn2c(N)nnc2c1CC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(N)nnc2c(CC)c1CC
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
6-Chloro-7,8-diethyl-[1,2,4]-triazolo[4,3-b]pyridazin-3-ylamine (W2.014, 0.1 g) was dissolved in ethanol (13 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (61 mg) and stirred at RT for 1 h, then at 55° C. for 30 min. Subsequently, a further 2 equivalents of sodium ethoxide were added and the mixture was stirred at 55° C. for 4.5 h. After another 1 equivalent of sodium ethoxide had been added, the mixture was stirred at 55° C. for 2.5 h and left to stand over the weekend. The solvent was then drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 92 mg of the title compound were obtained. LC-MS rt: 0.80 min [M+H]+: 236.2 (met. b)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.CN(C)[CH:19]=[O:20].[Cl-].[NH4+]>C(OCC)C>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:19]=[O:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc2ncccc2c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
n-Butyl lithium (19.2 mL; 1.5M hexane solution) was added dropwise to a solution of 6-bromoquinoline (5 g, 24.0 mmol) in diethyl ether (20 mL) that had been cooled to −70° C. under nitrogen atmosphere, a solution of N,N-dimethylformamide (3.7 mL, 48.0 mmol) in diethyl ether was further added, and the solution was stirred at −70° C. for 2 hours. The reaction solution was allowed to room temperature, then, an aqueous solution of saturated ammonium chloride was added, the solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (320 mg, 8.5%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[NH4+:12].[OH-]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]([NH2:12])=[O:11])=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: [NH4+]
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(Br)cc1CO
Reaction time: 36 h
Yield: 99 %

Procedure:
To a suspension of 5-bromoisobenzofuran-1(3H)-one III-1 (6.57 g, 30.1 mmol) in MeOH (140 mL) was added NH4OH (60 mL). The reaction vessel was sealed and stirred for 36 h. The reaction was The reaction was concentrated under vacuum to afford 4-bromo-2-(hydroxymethyl)benzamide (7.10 g, 99%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 7.80 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 2H), 7.61 (s, 1H), 7.59-7.50 (m, 2H), 6.34 (br s, 1H), 5.72 (br s, 1H), 4.64 (s, 2H); LC (254 nM) 1.12 min (>98%); MS (ESI) m/z=231.8.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 101 %

Procedure:
To a solution of benzyl 4-hydroxybenzoate (15.00 g, 65.1 mmol) in 130 mL acetone cooled in an ice water bath was added allyl bromide (11.4 mL, 130.1 mmol), followed by portionwise addition of potassium carbonate (45.00 g, 325.3 mmol). The ice bath was removed and the reaction mixture was warmed to rt. The mixture was stirred for 19 h. The precipitates were removed by filtration and the filtrate was concentrated to yield a colorless oil (17.65 g, 100%). LC/MS m/z 269 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.00-8.04 (m, 2H), 7.31-7.45 (m, 5H), 6.91-6.94 (m, 2H), 6.00-6.91 (m, 1H), 5.30-5.45 (m, 4H), 4.58-4.61 (m, 2H).
Reaction SMILES: C([O-])(=O)C.[Cu+2:5].C([O-])(=O)C.[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[NH2:10][CH2:11][C:12]([O-:14])=[O:13].[Cu+2:5].[NH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: NCC(=O)[O-]
Reaction time: 2 h

Procedure:
1.8 g (9.8 mmol) copper(II) acetate is dissolved in 100 ml hot methanol, and a solution of 1.5 g (20 mmol) glycine in 50 ml methanol is added with stirring. The solution becomes turbid due to precipitation of the product. Stirring is continued for two hours at a temperature causing precipitation. The precipitated product is filtered off and dried.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:17])=[CH:20][CH:21]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(Cn2cnc3cnccc32)cc1
Product: O=C(c1ccc(Cn2cnc3cnccc32)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
A suspension of ethyl 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)benzoate (0.50 g, 0.0018 mol) in morpholine (10 ml) was maintained at 150° C. in a bomb calorimeter for 3 days. The morpholine was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 10% ethanol in chloroform) and recrystallized from diethyl ether-ethyl acetate to yield [4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)phenyl](4-morpholinyl)methanone as a colorless crystalline solid, having a melting point of 188°-190° C. and the following physical characteristics:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].CO[CH2:24][CH2:25]OC>O>[CH:24]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15])=[CH2:25]
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1c(C#N)cnc2ccc(OC)cc12
Temperature: 85 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-3-quinolinecarbonitrile (1.1 g, 5.03 mmol), potassium carbonate (0.76 g, 5.53 mmol), tetrakis-triphenylphosphine (120 mg, 0.10 mmol) in DME (30 mL) and H2O (10 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (1.33 g, 5.53 mmol). After stirring for 5 hours at 85° C. the reaction contents was concentrated and the product purified by chromatography on silica gel (hexanes/EtOAc, 4:1) to give a light brown solid (0.9 g, 86%): LC/MS (ES) m/e 211 (M+H)+.