Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:12])[CH:3]=1.C[N:14](C=O)C>S(Cl)(Cl)=O>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:14])=[O:7])=[C:4]([I:12])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(I)c(C(=O)O)cc1C
Solvent: O=S(Cl)Cl
Product: Cc1cc(I)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
4,5-Dimethyl-2-iodobenzamide (4f) was obtained from 4,5-dimethyl-2-iodobenzoic acid 4c in two steps. To a solution of 2-iodo-4,5-dimethylbenzo ic acid 4c (1.2 g, 4.34 mmol) in thionyl chloride (20 ml) was added a catalytic amount of DMF, and the resulting solution was heated to redox for 2-3 hours. Excess thionyl chloride was removed under reduced pressure, and the crude acid chloride was dissolved in dry THF (10 ml) and transferred to a pressure vessel. After the addition of 38% aqueous ammonium hydroxide (20 ml), the pressure vessel was sealed and the reaction stirred at room temperature for 12 h. The reaction mixture was then concentrated and diluted with water (75 ml). The product was filtered and washed with water followed by washing with hexanes, and drying (in vacuo) to give the amide 4f (75%) as solid. mp 195-197° C., 1H NMR (400 MHz, DMSO-d6): δ 2.15 and 2.16 (2s, 6H), 7.11 (s, 1H), 7.40 (s, 1H), 7.61 (s, 1H), 7.70 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 19.23, 19.48, 90.12, 129.62, 136.92, 140.18, 140.26, 140.91, 171.25; HRMS (m/z): [M+H]+ calcd for C9H11INO, C9H11INO, 275.9880; found, 275.9878.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH3:14])=[N:8][N:7]2[C:15]=1[S:16]([NH2:19])(=[O:18])=[O:17])[CH3:2].C([O-])([O-])=[O:21].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].Cl.[OH2:39]>C(#N)C>[CH2:1]([S:3]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH3:14])=[N:8][N:7]2[C:15]=1[S:16]([NH2:19])(=[O:17])=[O:18])(=[O:21])=[O:39])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCc1ccc2nc(SCC)c(S(N)(=O)=O)n2n1
Reactant: O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: CCCc1ccc2nc(S(=O)(=O)CC)c(S(N)(=O)=O)n2n1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
2-Ethylthio-6-n-propylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.30 g, 1.00 mmol) was suspended in acetonitrile (1.0 ml) and water (4.0 ml), and sodium percarbonate (effective oxygen concentration, 12.2%; 0.33 g; 2.50 mmol) was added thereto at 45° C. and stirred at 50 to 60° C. for 2.5 hours. The reaction mixture was poured into water and acidified with dilute hydrochloric acid, and the precipitated insoluble solids were collected by filtration and washed with water, to give the title compound as white crystals. The yield was 0.25 g (75.3%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:8]=1[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>CC(CC)=O>[ClH:3].[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:9](=[O:11])[C:8]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:7]=1[O:6][CH3:5])[CH3:33]
Reactant: O=S(Cl)Cl
Reactant: CCN1CCCC1CN
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CCN1CCCC1CNC(=O)c1c(OC)cccc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30 ml of thionyl chloride is added to 18.2 g (0.1 mol) of 2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for 30 minutes. To the solution is added 50 ml of toluene. The solvent and excess thionyl chloride is evaporated at reduced pressure. The residue is dissolved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise while stirring to 12.8 g (0.1 mol) of 2-(aminomethyl)-1-ethyl-pyrrolidine in 50 ml methylethyl ketone. After the addition the mixture is stirred for 30 minutes at room temperature. The obtained precipitate is filtered off, washed with ether and recrystallized from ethanol - isopropyl ether. Yield: 26.7 g, m.p. 182°-84° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:11]O>S(F)(=O)(=O)O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:11].[C:9]1([OH:11])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: OO
Agent: O=S(=O)(O)F
Product: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12
Reaction time: 0.5 h
Yield: 3 %
Yield: 37 %

Procedure:
To a vigorously stirred suspension of 0.1 mol of naphthalene in 100 ml of fluorosulfuric acid at -78° C. was added an equally cold solution of 0.12 mol of H2O2 (90% solution) in 100 ml of fluorosulfuric acid. The reaction mixture was stirred for 30 minutes, then quenched with ice water, and worked up and analyzed as in Example 1. 39% naphthalene was recovered unchanged. 37% of β-naphthol and 3% of α-naphthol were obtained, together with 17% of dihydroxynaphthalenes and 5% polymeric material.
Reaction SMILES: [F-].[K+].Cl[C:4]1[C:9]([S:10]([N:13]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[C:14]2[C:19]([O:20][CH3:21])=[N:18][C:17]([CH3:22])=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(OCC)(=O)C>O.C1(C)C=CC=CC=1.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>[CH2:26]([O:25][C:23]([N:13]([C:14]1[C:19]([O:20][CH3:21])=[N:18][C:17]([CH3:22])=[CH:16][N:15]=1)[S:10]([C:9]1[C:4]([C:37]2[CH:38]=[CH:39][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][CH:36]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)(=[O:12])=[O:11])=[O:24])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Yield: 82.6 %

Procedure:
A solution of potassium fluoride (7.0 g) in water (150 ml) was added to a solution of 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (8.3 g), 4-methoxycarbonylphenylboronic acid (7.9 g) and tetrakis(triphenylphosphine)palladium(0) (1.0 g) in toluene (150 ml) and the mixture was heated under reflux under argon for 18 hours. Ethyl acetate (150 ml) was added and the organic phase was separated. The solution was washed with 2M sodium hydroxide solution (100 ml) and water (250 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was triturated with ethyl acetate/hexane (1:3 v/v) to give N-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (8.5 g), m.p. 134-136° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:61])[N:40]([CH2:44][CH:45]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[C:46]1[CH:47]=[N:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[CH2:41][CH2:42][OH:43])([CH3:37])([CH3:36])[CH3:35].[N+:62]([C:65]1[CH:70]=[CH:69][C:68](O)=[CH:67][CH:66]=1)([O-:64])=[O:63]>C1COCC1>[C:34]([O:38][C:39](=[O:61])[N:40]([CH2:44][CH:45]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[C:46]1[CH:47]=[N:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[CH2:41][CH2:42][O:43][C:68]1[CH:69]=[CH:70][C:65]([N+:62]([O-:64])=[O:63])=[CH:66][CH:67]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1)CC(O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
To a cooled (0° C.), stirred solution of triphenylphosphine (629 mg) in THF (6 mL) was added diisopropylazodicarboxylate (0.5 mL) dropwise and the resulting thick white slurry was stirred for 45 min. A solution of [2-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester (515 mg) and 4-nitrophenol (332 mg) in THF (5 mL) was added dropwise to produce a yellow slurry. After an additional 1 h period, the cooling bath was removed and the mixture was allowed to stir at ambient temperature for 20 h. This mixture was concentrated in vacuo and chromatographed on a Biotage® F40M column (gradient of 10% to 15% ethyl acetate/hexanes) to afford 530 mg of the title compound (I-3c) as a colorless foam.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][C:36]1([OH:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[OH:42][C:36]1([CH2:35][NH:34][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=2)=[O:18])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NCC1(O)CCCCC1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC2(O)CCCCC2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and 1-(aminomethyl)cyclohexanol, the title compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=451.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8]P(OCC)(OCC)=O)(=[O:5])[CH3:4].[Br:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.C(OCC)C>C1COCC1>[Br:17][C:18]1[N:23]=[C:22]([CH:24]=[CH:4][C:3]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
In THF (10 ml) was suspended sodiumhydride (60%, 440 mg, 11.0 mmol), and to the mixture was added at -30° C. a solution of diethylphosphonoethyl acetate (2.47 g, 11.0 mmol) in THF (10 ml). The mixture was stirred at the same temperature for 30 minutes, and to the mixture was added at -30° C. a solution of 6-bromo-2-pyridinecarbaldehyde (1.86 g, 10.0 mmol) in THF (10 ml). While warming the temperature of the mixture from -30° C. to -10° C., the mixture was stirred for 1.5 hours. To the mixture was added diethylether (40 ml), and the mixture was washed with water (20 ml, 5 ml×2) and saturated brine (5 ml). The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added hexane (10 ml), and the mixture was cooled to 0° C. The precipitated insoluble materials were filtered, which were washed with hexane cooled to 0° C., and dried under reduced pressure to give ethyl 6-bromo-2-pyridineacrylate (2.00 g, 7.81 mmol, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=2[I:16])=[O:8])[CH2:4][O:3]1.[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>>[C:30]([O:33][CH2:34][CH2:35][N:9]([C:10]1[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=1[I:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:29])([CH3:1])[O:6]1)=[O:8])(=[O:32])[CH3:31]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C2COC(C)(C)O2)c1I
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I

Procedure:
5-(2,2,-Dimethyl-1,3-dioxolane-4-carbamido)-2,4,6-triiodo-1,3-di-(acetoxymethyl) benzene was alkylated with 2-bromoethyl acetate according to Example 30a. The crude product, containing some O-alkylated material was used directly in next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:22]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NCCCN1CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCN1CCCNC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
34.3 g (237 mmol) of 1-(2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one (patent; Chem. Werke Huels; DE 1121617; 1962; Chem. Abstr.; EN; 56; 11601 g; 1962) are dissolved in 612 ml of DMF and admixed with 36.1 g (356 mmol) of triethylamine, 1.45 g (11.9 mmol) of DMAP and 85.0 g (309 mmol) of tert-butyl(chloro)diphenylsilane, and stirred at RT for 18 h. Then the mixture is added to 2000 ml of water and extracted three times with dichloromethane. The combined organic phases are washed twice with water and then dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is recrystallized from acetonitrile. This affords 71.9 g (78% of theory) of the desired compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]O)=[CH:19][CH:18]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CNC1=NS(=O)N=C1NCCS
Reactant: CN(C)Cc1ccc(CO)o1
Agent: Cl
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
When 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared in Step A] is treated with about one equivalent of 5-dimethylaminomethyl-2-furanmethanol in concentrated hydrochloric acid according to the procedure described in Example 25, Step B, the title compound is thereby produced; identical to the product of Example 18.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22]/[C:21](=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])/[CH2:20]1)[CH3:18]
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C1\C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at rt. After about 30 min, a solution of (3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.300 g, 0.708 mmol, Preparation #25) in THF (1 mL) was added. After about 4 h, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) were added. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc/heptane/DCM (2:1:1) to provide (E)-ethyl 2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.260 g, 74%). LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 494 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C(C([Sn])=C(CC[CH2:31][CH3:32])CCCC)CCC.CN(C=[O:38])C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH2:32][CH2:31][OH:38])[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(Br)cnc21
Reactant: CN(C)C=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc2cc(CCO)cnc21
Temperature: 95 °C
Yield: 97 %

Procedure:
To a solution of 6-bromo-3-(2-trimethysilylethoxymethyl)-3H-imidazo-[4,5-b]-pyridine (1.3 g, 4 mmol) and bis(triphenylphosphine)-palladium (II) chloride in DMF (12 mL) was added tributylvinyl tin (2.14 g, 6.7 mmol). The reaction vessel was evacuated-purged (N2) several times followed by heating to 95° C. for 15 h. After cooling, the crude reaction mixture was filtered through a pad of celite® and eluted with ethyl ether. The ethereal mixture was washed several times with saturated KF, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel using a gradient elution of ethyl acetate/hexanes (10, 20, 30 to 40%) which provided 1.06 g of the title compound (97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27]>C(Cl)Cl.O1CCCC1>[ClH:1].[NH2:27][CH2:26][CH2:25][NH:28][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1]
Reactant: NCCN
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: NCCNC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Yield: 52.7 %

Procedure:
19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine. 10 ml (0.1 mol) of ethyl chloroformate are then added dropwise at 0°. After completion of the addition (0.5 hour), the mixture is poured on to ice/water. The methylene chloride phase is separated, dried over magnesium sulfate and concentrated to about 30 ml. This solution is added dropwise at 0° to a solution of 20 ml (0.3 mol) of ethylenediamine in 100 ml of tetrahydrofuran. After completion of the addition (0.5 hour), the mixture is filtered, the filtrate is acidified with dilute hydrochloric acid the neutral constituents are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloroform phases, the residue is converted into the hydrochloride. After recrystallization from ethanol/ether, there are obtained 7.1 g of N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride, m.p. 179°-182°.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][NH:7][C:8]([NH2:10])=[NH:9].O.[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[O:15][CH2:16][CH:17]=O>C(O)(=O)C.C(O)C>[C:8]([NH:7][N:6]=[CH:17][CH2:16][O:15][C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[Cl:12])(=[NH:10])[NH2:9].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: N=C(N)NN
Reactant: O=S(=O)(O)O
Reactant: O=CCOc1ccccc1Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)NN=CCOc1ccccc1Cl
Product: O=S(=O)([O-])[O-]

Procedure:
A solution of 3.3 g of aminoguanidine sulphate in 30 ml. of water is added to a solution of 2.8 g. of o-chlorophenoxy acetaldehyde in 30 ml. of ethyl alcohol at 95°. Heating is effected under reflux for 4 hours, with addition of a few drops of acetic acid. After cooling, a solid product precipitates and it is separated and washed with very little water followed by ethanol. Recrystallisation is effected in the water-ethanol mixture (1/1). The o-chlorophenoxy acetaldehyde guanyl hydrazone is obtained in the form of sulphate, m.p.=198° C., with a yield of 90%.
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][O:7][N:8]=1>CC(C)=O>[I-:2].[Cl:3][C:4]1[C:5]([C:9]2[CH:10]=[N+:11]([CH3:1])[CH:12]=[CH:13][CH:14]=2)=[N:6][O:7][N:8]=1
Reactant: Clc1nonc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nonc2Cl)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (230 mg, 1.2 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 h and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16]([OH:18])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([C:16](=[O:18])[NH:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)C1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 96.3 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxy-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.96 mmol) and β-phenethylamine (133 μL, 1.061 mmol) to give 383 mg of the title compound (96%): mp 246°~249° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.01 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.25 (m, 5H), 7.22 (d, 1H, J=1 Hz), 7.07 (d, 1H, J=1 Hz), 5.07 (dd, 1H, J=10, 5 Hz), 3.65 (dd, 1H, J=17, 10 Hz), 3.30 (dt, 2H, J=5.6, 7 Hz), 3.04 (dd, 1H, J=17, 5 Hz), 2.71 (t, 2H, J=7 Hz).
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[NH2:10]>>[C:1]([NH:10][C@@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(O)C(=O)O
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 120 °C

Procedure:
Lactic acid (30 g) and glucosamine (10 g) were mixed and heated for 4 hours at 120° C. The reaction mixture was cooled and washed with ethyl acetate. The residue (25 g) was dissolved in 100 g of water.
Reaction SMILES: S(Cl)(Cl)=O.BrCC1C=CC(C(O)=O)=CC=1.BrCC1C=CC(C(Cl)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[Br:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][C:58]([N:60]=[C:61]=[S:62])=[O:59])=[CH:53][CH:52]=1>C1(C)C=CC=CC=1.C(O)C>[Br:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][C:58]([NH:60][C:61]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][CH:33]=3)=[CH:43][CH:44]=2)=[S:62])=[O:59])=[CH:55][CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cc1ccc(CBr)cc1)N=C=S
Agent: O=C(Cl)c1ccc(CBr)cc1
Agent: O=C(O)c1ccc(CBr)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(CBr)cc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-(bromomethyl)benzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-[4-(bromomethyl)phenyl]ethanoyl isothiocyanate was prepared using the resultant 4-(bromomethyl)-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-[4-(bromomethyl)phenyl]ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 52%).