Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[P:13]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:37]>CO.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:37])[NH2:36])=[CH:33][CH:34]=1)[P:13]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: N=C(N)c1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was synthesized according to (8) with slight modifications. The iminoester prepared from diphenyl [N-(benzyloxycarbonyl)amino](4-cyanophenyl)methane phosphonate (1.5 g, 3.0 mmol) was dissolved in a mixture of methanol (30 ml) and 0.5 M NH3 in 1,4-dioxane (15 ml), the solution stirred at room temperature overnight, solvent was removed and the oily residue dissolved in CHCl3 (30 ml). Diethyl ether (100 ml) was added, the precipitate collected by filtration, washed with diethyl ether (30 ml×5) and dried in vacuo [yield 1.2 g (73%)]. The crude product was judged sufficiently pure for biotinylation. For use in kinetic studies, further purification was carried out by HPLC (100 mg crude 1) yielding 36 mg 1. [tR 31.58 min, purity 99% (A:B 80:20 to 20:80 in 60 min); m/z (ESI) 516 (M+H)+, 1031 (2M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:4]([O:3][CH2:1][CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: BrBr
Reactant: CCOc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4′-[(2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (6.15 g) and sodium acetate (1.46 g) in acetic acid (100 mL) was added bromine (0.91 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (7.12 g, 94%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH:15]=[CH2:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:19].[Na].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:18])([CH3:17])[CH2:15][CH2:16][NH2:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: N
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
24.2 g of 3-(4'-fluoro-4-biphenylyl)-1-buten-3-ol (obtainable from 4-acetyl-4'-fluorobiphenyl and vinylmagnesium bromide) are heated with 8 g of ammonia and 0.25 g of sodium for 8 hours at 180° - 200°, and the mixture is cooled and worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144° - 146°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:4]1[CH:3]=[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: CC1(C)OBOC1(C)C
Reactant: Nc1ccc(Br)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Temperature: 80 °C

Procedure:
Dissolve 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol) in dioxane (80 mL) in a RBF under nitrogen. Add triethylamine (10 mL, 3.6 equiv.) then sparge with nitrogen to de-gas. Add 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 2.9 equiv.) dropwise via syringe over approximately 5 minutes. Sparge an additional 5 minutes with nitrogen then add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.603 g, 3.7 mol %, 1:1 complex with dichloromethane). Place under nitrogen and heat at 80° C. overnight. After the reaction cools, filter via Celite® washing with hexanes. Concentrate filtrate to dryness and use crude.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(Cl)CCl.[CH2:22]([O:29][CH2:30][C:31](O)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:6]=2[N:14]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: NC(=O)c1cc2c3ccccc3n(C(=O)COCc3ccccc3)c2nc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 21.8 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 150 mg, 0.663 mmol) in pyridine (7 mL) was added EDC (210 mg, 1.10 mmol), DMAP (85 mg, 0.693 mmol) and benzyloxyacetic acid (142 μL, 0.994 mmol) and the mixture was stirred at RT under an atmosphere of Ar. After 23 h, the reaction was quenched with water (20 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with water (75 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-[(benzyloxy)acetyl]-9H-pyrido[2,3-b]indole-3-carboxamide (28, 54 mg, 22%). NH4OAc standard conditions. DAD Retention time=7.6 min. M+H=375. 1H NMR (300 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.52-8.49 (m, 1H), 8.04 (br s, 1H), 7.83-7.77 (m, 3H), 7.47-7.29 (m, 8H), 5.30 (s, 2H), 4.72 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH:31]3[NH:35][CH2:34][CH2:33][S:32]3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:35]1[CH2:34][CH2:33][S:32][CH:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH2:21][CH2:20]1)=[O:8])=[O:5])[CH3:2]
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: CCOC(=O)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
0.9 g of ethoxycarbonyl isocyanate is added to a solution of 2 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine in 30 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 18 hours. 3.1 g of ethoxycarbonyl isocyanate are added to the mixture, and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture, and the aqueous mixture is made alkaline with potassium carbonate. The aqueous mixture is extracted with ethyl acetate, and the extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, benzene:ethyl acetate=1:1). 1.05 g of N-ethoxycarbonyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained as an amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+].[Br-]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargy bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)CCC>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)[CH:3]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)cc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccc(Nc2nc(NC3CCCCCC3)cc(N3CCC(O)CC3)n2)cc1Cl
Yield: 23 %

Procedure:
To a solution of compound 6-chloro-N2-(3-chloro-4-methoxy-phenyl)-N4-cycloheptyl-pyrimidine-2,4-diamine (0.15 g, 0.39 mmol) in 1-butanol (5 mL) was added 4-hydroxypiperidine (0.12 g, 1.18 mmol) at 25° C. with stirring. To this triethylamine (0.43 mL, 3.15 mmol) was added dropwise and the mixture was stirred at 25° C. for 30 minutes. This was heated and refluxed for 12 hours under nitrogen atmosphere. The mixture was concentrated under vacuum, diluted with cold water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were collected, combined, washed with brine (30 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired compound. Yield: 23%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:57]1[CH:61]=[C:60]([CH2:62][C:63]2[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=2)[N:59]=[CH:58]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:59]2[C:60]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=3)=[CH:61][N:57]=[CH:58]2)=[CH:8][N:7]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2cccs2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3cccs3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH3:12]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CNc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution at 0° C. of 5-chloro-2-nitroaniline (100 g) in dimethylformamide (1.0 l) was added potassium t-butoxide (70.3 g) and the mixture was stirred at 0° C. for 1 hour. To the reaction mixture was added dropwise a solution of dimethyl sulfate (62 ml) in dimethylformamide (100 ml) and the resulting mixture was stirred at 25° C. for 1.5 hours to afford a solution of 5-chloro-N-methyl-2-nitroaniline in dimethylformamide. To the resulting mixture was added 24% sodium methoxide in methanol (230 ml) and the mixture was heated at 55° C. for 2 hours with stirring. At the end of this time the reaction mixture was cooled to 25° C. and water (1.5 l) was added. The precipitated crystals were collected by filtration and washed with water and methanol to give the desired compound (94.5 g, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
In a 250-ml, round-bottomed flask equipped with a heating mantle, magnetic stirrer, condenser and Dean Stark trap, were placed 2.5 g (16.0 mmol) of 3-fluoro-4-hydroxybenzoic acid, ten g (113.4 mmol) of (S)-2-methyl-1-butanol, 0.347 g of p-toluenesulfonic acid monohydrate and 100 ml of benzene. The reaction mixture was stirred overnight under reflux. The reaction mixture was extracted using saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered through cotton and evaporated to an oil. The product was purified by flash chromatography on silica gel with 3% diethyl ether in dichloromethane. Fractions containing the desired product were combined and evaporated to a pale-yellow oil. Analysis by NMR showed that considerable starting alcohol remained. The oil was placed under vacuum (at 70° C.) for two days. No alcohol was shown by gas chromatography to be present. The desired product was obtained in the amount of 2.39 g (66% yield) and had the following structure. ##STR30##
Reaction SMILES: [CH3:1][O:2]N=C1C(COS(C)(=O)=O)(CO)CN(CC2C=CC=CC=2)C1.[CH2:24]([N:31]1[CH2:35][CH:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33](=[O:41])[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].C=O>C(O)(C)C>[CH2:24]([N:31]1[CH2:35][C:34]([CH2:1][OH:2])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33](=[O:41])[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CON=C1CN(Cc2ccccc2)CC1(CO)COS(C)(=O)=O
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOC(=O)C1(CO)CN(Cc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
1-benzyl-4-methanesulfonyloxymethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime 50 g of 1-benzyl-4-ethoxycarbonyl-pyrrolidine-3-one was dissolved in 300ml of isopropanol and thereto 4 ml of 10% NaOH and 20.7 ml of formalin were added successively. The mixture was stirred for 30 minutes at room temperature and concentrated under the reduced pressure. 200 ml of water was added to the concentrated residue. The resulting solution was extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduce pressure to give 46 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one(yield : 82.0%). The obtained compound was dissolved in 400 ml of pyridine and thereto methoxylamine hydrochloride was added and stirred for 1 hour at room temperature. The reaction mixture was concentrated under the reduced pressure, diluted with 400 ml of dichloromethane, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 43 g of 1-benzyl-4-hydroxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime (yield: 84.6%). Thus obtained compound was dissolved in a solution of 22 ml of triethylamine and 400 ml of dichloromethane and cooled to 0-5° C. and thereto 10 ml of methanesulfonylchloride was added dropwise and the reaction temperature was slowly increased up to room temperature. The reaction mixture was stirred for 1 hour, washed with water and saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 50 g of 1-benzyl-4-methanesulfonyloxymethyl-4-ethoxycarbonyl-pyrroline-3-one-O-methyloxime (yield : 92.6%). It was dissolved in 200 ml of tetrahydrofuran and thereto 13 g of sodium borohydride and 400 ml of ethyl alcohol were added successively at room temperature and 11 g of lithium chloride was added slowly. The reaction mixture was stirred for 5 hours and poured into 300 ml of ice water. The resulting solution was adjusted to pH 5-6 with diluted hydrochloric acid, concentrated under the reduced pressure to remove most organic solvents therefrom, then extracted twice with each 200 ml of ethylether, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by silicagel column chromatography(ethylacetate:normal hexane=2:1) to give 42 g of the titled liquid compound (yield: 94.3%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1.Cl.[NH2:17][OH:18].O>CN1CCCC1=O>[OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=[N:17][OH:18])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1
Reactant: NO
Reactant: O=C1C(=NOCCO)Oc2ccccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 37.8 %

Procedure:
At 80° C., 10.1 g (0.05 mol) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) in 50 ml of N-methyl-2-pyrrolidinone are stirred with 3.5 g of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is then chromatographed over silica gel using tert-butyl methyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 4.2 g (29.6% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-oxime consisting of 62.4% of isomer A and 15.8% of isomer B (HPLC).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=[C:2]([NH:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc2c(Cl)ncc(-c3cccnc3)c2s1
Reactant: Cc1nc(N)cs1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(Nc2ncc(-c3cccnc3)c3sc(C)nc23)cs1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-methyl-7-pyridin-3-yl-thiazolo[4,5-c]pyridine (100 mg, 0.38 mmol) and 4-amino-2-methylthiazole (44 mg, 0.38 mmol) (Example C) were dissolved in 3 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (44 mg, 0.08 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added and this mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Tris(dibenzylideneacetone)dipalladium chloroform complex (38 mg, 0.035 mmol) was added and the reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->0:100 gradient) and recrystallization in diisopropylether. The desired product was obtained as a yellow solid (20 mg, 15%), MS: m/e 354.1 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][CH:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)Nc1ccc(S[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Yield: 25 %

Procedure:
If the procedure described in Preparation IV is followed starting from 4.5 g (27.10-3 mol) of N-(4-mercaptophenyl)acetamide, 11.43 g (32.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2.16 g (27.10-3 mol) of zinc oxide (ZnO), 3 g (yield: 25%) of the expected product are obtained after recrystallization from a toluene/isopropyl ether mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].O.[NH2:22]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:22]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]carbamate (i.e. the product of Step A) (4.14 g, 13.9 mmol) in methanol (80 mL) was added hydrazine hydrate (0.771 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solid collected was dried under reduced pressure to provide the title compound, a compound of the present invention, as a solid (3.26 g).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:33])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:15]([S:24](C)(=O)=O)[N:16]3[CH:21]3[CH2:23][CH2:22]3)=[CH:11][C:10]=2[F:34])[CH2:5]1)[CH3:3].O.[SH-].[Na+]>COCCOC.O>[NH2:1][C@H:2]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:33])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:15]([SH:24])[N:16]3[CH:21]3[CH2:22][CH2:23]3)=[CH:11][C:10]=2[F:34])[CH2:5]1)[CH3:3]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC)c(N3CC[C@@H]([C@H](C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(N3CC[C@@H]([C@H](C)N)C3)c(F)cc2c1=O

Procedure:
Compound 18 from previous reaction is partially dissolved in DME (150 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich, 72.6% by titration, 4.65 g, 60.2 mmol) in water (15.0 mL) is added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≦2% of 18 remains) after 15 h. Excess sodium hydrosulfide is quenched upon addition of aq HCl (30 mL, 6 N). The resulting orange solution (pH ˜2) is sparged with argon (3 h) to remove the generated hydrogen sulfide.