Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: Oc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 39.4 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.511 g, 2.06 mmol) and commercially available 3-aminophenol 8 (0.225 g, 2.06 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenol 32 (0.26 g, 40% yield) as a solid. MS (ES) m/z 321 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH:10]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:12]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
reacting L-aspartic acid with formic acid in the presence of an effective amount of acetic anhydride under conditions sufficient to form N-formyl-L-aspartic anhydride; and thereafter
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[C:25]([F:26])=[CH:24][C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[C:25]([F:26])=[CH:24][C:20]4[S:21][CH:22]=[CH:23][C:19]=4[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Fc1cc2sccc2cc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc3ccsc3cc2F)CCN1c1cnccc1C1CC1
Yield: 5.7 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 90 g, 0.443 mmol) was reacted with 5-bromo-6-fluorobenzo[b]thiophene (I-28d: 102 mg, 0.443 mmol), 1,4-dioxane (4 mL), copper iodide (9 mg, 0.044 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (19 mg, 0.132 mmol) and potassium phosphate (282 mg, 1.329 mmol) to afford the crude product. Purification by preparative HPLC afforded 9 mg of the product (6% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5](=[O:14])[NH:4]1.[CH3:15]I>C1COCC1>[CH3:15][N:4]1[C:5](=[O:14])[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:3]1
Reactant: CI
Reactant: O=C1CCc2ccccc2CN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2ccccc2CCC1=O
Reaction time: 0.17 h
Yield: 95 %

Procedure:
At 25° C., sodium hydride (150 mg, 6.3 mmol) was added to a solution of 1,2,4,5-tetrahydro-benzo[c]azepin-3-one (1 g, 6 mmol) in THF (50 mL). The suspension was stirred for 10 minutes and treated with methyl iodide (1 g, 7 mmol). The mixture was stirred for an additional 4 hours and then partitioned between ethyl acetate (100 ml) and water (50 ml). Washing once with brine (30 ml), drying over anhydrous magnesium sulfate and evaporation of solvent gave 2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one (1 g, 5.7 mmol, 95%): 1H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.52 (s, 2H), 3.18 (t, 2H), 3.09 (s, 3H), 3.00 (t, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:21][OH:22].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]([OH:22])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(Nc2ccccc2CNO)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(O)Cc1ccccc1Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Acetyl chloride (0.53 g, 6.8 mmol) is added dropwise at 0° C. to a solution of 2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzenemethanamine (1.64 g, 6.8 mmol) and sodium acetate (840 mg, 0 mmol) in 2:1 dioxane/water (100 ml). The reaction mixture is stirred at room temperature for 30 minutes. The product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated to a residue which is recrystallized from cyclohexane to give pure N-[[2-[(2,3-dimethylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide (1.02 g, 53%); mp 93°-98° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C.[OH:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1.[Br:44][CH2:45][CH2:46]O>C1(C)C=CC=CC=1>[Br:44][CH2:45][CH2:46][O:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1
Reactant: Oc1cc(-c2ccccc2)on1
Reactant: OCCBr
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Triphenylphosphine (15.7 g) was dissolved in toluene (200 ml), and the solution was cooled to 5° C. Diethyldiazodicarboxylate (10.4 g) was added to the solution, and the resulting mixture was stirred at the same temperature for 10 minutes. Then, 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) were added in this order to the reaction mixture, followed by stirring of the resulting mixture at room temperature for 10 minutes and further at room temperature for 2 hours. Insolubles were filtered off from the mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (12.1 g, 90%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:5]Cl)[CH2:4][O:3]1.[C-:7]#[N:8].[Na+].[C-:10]#[N:11].[K+]>Cl.O>[C:7]([CH2:4][C:2]([CH3:1])([OH:3])[CH2:5][C:10]#[N:11])#[N:8]
Reactant: [C-]#N
Reactant: CC1(CCl)CO1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(O)(CC#N)CC#N
Temperature: 40 °C
Reaction time: 10 h
Yield: 96.7 %

Procedure:
To a solution of 2-methyl-2-chloromethyloxirane (50 g; 0.47 mol) in concentrated hydrochloric acid (23 ml) at ice-bath temperature was added a solution of sodium cyanide (27.4 g; 0.56 mol) in hydrochloric acid (23 ml). After stirring for 10 hours at that temperature, the reaction mixture was warmed to 40° C. and a solution of potassium cyanide (33.8 g; 0.52 mol) in water (50 ml) was added. The reaction mixture was warmed to 50° C. and stirred for 4 hours. After cooling, the mixture was neutralized and extracted 3 times each with ethyl acetate (150 ml). The combined extracts were dried with anhydrous magnesium sulphate. Removal of the solvent in vacuo afforded 1,3-dicyano-2-methyl-2-hydroxypropane (56.4 g; 96%). This compound was added carefully to a 33% wet solution of hydrogen bromide in glacial acetic acid at ice-bath temperature. The reaction mixture was stirred for 3 days at ambient temperature. The solvent was removed in vacuo and the residual oil brought to pH 12 with a 10 molar aqueous solution of sodium hydroxide. The alkaline solution was extracted 3 times each with ethyl acetate (100 ml). The extracts were combined and the solvent removed in vacuo to afford 6-amino-2-bromo-4-methylpyridine (56 g; 66%) as colorless crystals. Melting point 99° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[S:11][CH:12]=1)[C:5]([OH:7])=O.C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:57](=[O:58])[N:34]2[C:35]([C:54]([OH:56])=[O:55])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][C:47]([C:51]([OH:53])=[O:52])=[N:48][O:49][CH3:50])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.O.CC(C)=O.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[S:11][CH:12]=1)[C:5]([NH:31][CH:32]1[C:57](=[O:58])[N:34]2[C:35]([C:54]([OH:56])=[O:55])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][C:47]([C:51]([OH:53])=[O:52])=[N:48][O:49][CH3:50])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Reactant: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1)C(=O)O
Agent: C[N+](C)=CCl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1)C(=O)O
Reaction time: 0.5 h

Procedure:
2-Methoxyimino-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (0.97 g) was added at 0° C. to vilsmeier reagent which had been prepared from N,N-dimethylformamide (0.31 g) and phosphoryl chloride (0.65 g) in ethyl acetate (1.2 ml) and tetrahydrofuran (7.4 ml), and the mixture was stirred at the same temperature for 30 minutes to afford the activated solution. The activated solution was added dropwise at -5 to 0 C. to a solution of 7-amino-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (1.40 g) in water (10 ml) and acetone (8 ml), adjusted to pH 8.0 with sodium bicarbonate and the mixture was stirred at the same temperature for 45 minutes. To the resultant mixture was added ethyl acetate (10 ml), and the aqueous phase was separated from the mixture. To the aqueous solution was added ethyl acetate (70 ml) and the mixture was adjusted to pH 2.0 with 10% hydrochloric acid with stirring, and the ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was pulverized with diisopropyl ether to give 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxy-2-methoxyiminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer: in the 7-position) (1.77 g), mp 164° to 170° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:20]([N:3]1[CH2:4][CH:2]1[CH3:1])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are at room temperature overnight. The mixture is poured into 10% citric acid and is extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2-methyl aziridine.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15]>C(Cl)Cl>[Br:11][C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[CH2:14][OH:15]
Reactant: COC(=O)c1ccncc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1ccncc1Br
Temperature: -15 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Diisobutylaluminum hydride (1.0M solution in tetrahydrofuran, 14 mL) was added to a solution of methyl 3-bromoisonicotinate (1.0 g, 4.6 mmol) in methylene chloride (15 mL) cooled at −15° C. After 1 hour at this temperature, the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride solution (3 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid solution in water (20 mL). The organic layer was separated, and the aqueous layer was neutralized via addition of solid sodium bicarbonate solution and then extracted with ethyl acetate (50 mL). The combined organic portions were dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-75% ethyl acetate in heptane) to afford the title compound as a white solid (110 mg, 75%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[OH-].[Na+:18].O.O.O.C([O-])(=O)C.[Na+].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>O>[Na+:18].[OH:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=3)(=[O:37])=[O:38])[CH:3]=2)[CH:8]=[C:7]([S:12]([O-:15])(=[O:13])=[O:14])[CH:6]=1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3cc(S(=O)(=O)[O-])cc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 11.95 g of 6-amino-4-hydroxy-2-naphthalenesulfonic acid in 200 ml of water was adjusted to pH 8.0 with aqueous 5N sodium hydroxide, then 12.17 g of sodium acetate trihydrate was added to the stirred mixture followed by 15.06 g of p-nitrobenzenesulfonyl chloride. The mixture was stirred vigorously under nitrogen at room temperature for 16 hours producing a yellow solid. The mixture was filtered and the solid was washed with water, ethanol and then ether and dried in vacuo and gave 12.07 g of 4-hydroxy-6-p-nitrobenzenesulfonamido-2-naphthalenesulfonic acid sodium salt as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH2:10])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(CN)cc1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of 4-butylbenzonitrile (3.63 g, 22.8 mmol) in THF (10 mL) was placed in a three-neck round bottom flask equipped with a Vigreux column and short-path distillation head. The solution was heated to reflux and BH3-methyl sulfide complex (2.0 M in THF, 15 mL, 30 mmol) was added dropwise over 15 minutes. Methyl sulfide was distilled off from the reaction mixture over 1 h and the solution was cooled to room temperature. Aqueous HCl (6N, 25 mL) was added slowly via an addition funnel and the mixture was heated at reflux for 30 minutes. The reaction was cooled to 0° C. and NaOH (7.0 g) was added portionwise. The aqueous solution was washed with EtOAc (3×) and the organic solution was dried (MgSO4), filtered, and concentrated to provide the title compound of Method A (4.01 g). 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 2H), 7.24 (m, 2H), 4.04 (s, 2H), 2.62 (t, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.C[Si](C=[N+]=[N-])(C)C.Cl.BrCC(C1C=CC(Br)=C(F)C=1)=O.[Cl:32][CH2:33]C(C1C=CC(Br)=C(F)C=1)=O>C(#N)C.C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH2:33][Cl:32])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(CCl)c1ccc(Br)c(F)c1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: O=C(CBr)c1ccc(Br)c(F)c1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CCl)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoyl chloride (33 g, CAS 151982-51-3) in acetonitrile (150 ml) and THF (150 ml) at 0-5° C. was added dropwise (trimethylsilyl)diazomethane (83.4 ml, 2 M solution in hexane). The reaction mixture was stirred at room temperature for 30 min. TLC analysis showed the reaction was complete. 37% Hydrochloric acid (23.2 ml) was then added dropwise at 0-5° C. and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into EtOAc and extracted sequentially with aq. Na2CO3 solution, water and saturated brine. The organic layer was then dried over Na2SO4 and concentrated in vacuo to afford a ca 1:1 mixture of 2-bromo-1-(4-bromo-3-fluoro-phenyl)-ethanone and 2-chloro-1-(4-bromo-3-fluoro-phenyl)-ethanone (34.4 g, 98%) as a yellow solid which was used in the next step without further purification. MS (EI): 203 ([{81Br}M-CH2Cl]+, 201 ([{79Br}M-CH2Cl]+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[N:33][NH:34]2)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:34]3[C:35]4[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:36]=4)[CH:32]=[N:33]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Temperature: 125 °C
Yield: 56.6 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, 468 μmol), 6-methoxy-1H-indazole (69.3 mg, 468 μmol) in dioxane (3.5 mL) was added sodium tert-butoxide (98.9 mg, 1.03 mmol) and bis(tri-tert-butylphosphine)palladium(0) (23.9 mg, 46.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-30% ethyl acetate in hexanes) gave N-tert-butyl-2-(6-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (131 mg, 57%). 1H NMR (CDCl3) δ: 9.06 (s, 1H), 8.33 (s, 1H), 8.18 (d, J=0.8 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.01 (dd, J=8.8, 2.3 Hz, 1H), 5.71 (s, 2H), 3.94 (s, 3H), 3.53-3.63 (m, 2H), 1.57 (s, 9H), 0.91-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11]Cl.[CH2:14]([CH:23]1[S:27][CH:26]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[NH:25][C:24]1=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+].[Cl-]>CN(C)C=O>[CH3:8][N:9]([CH3:13])[CH2:10][CH2:11][N:25]1[C:24](=[O:34])[CH:23]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:27][CH:26]1[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(C)CCCl
Reactant: CCCCCCCCCC1SC(c2cccnc2)NC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 10 h
Yield: 33.3 %

Procedure:
K2CO3 (0.9 g, 6.52 mmol) and 2-dimethylaminoethyl chloride hydrochloride (0.47 g, 3.26 mmol) were added to a solution of 5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (1 g, 3.26 mmol) in dry dimethylformamide (10 ml). The mixture was kept at 50° C. for 10 hours. The resulting mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.41 g, 0.41 g, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN(C)C(=O)N1CCNCC1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide using General Procedure B-3 yielded 4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[C:5](=[O:10])[CH:6]([Br:12])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCC(O)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)C(=O)C(=O)OCC

Procedure:
In a modification of the method described in JCS Perkin Trans. I 1972, 2584, a mixture of 2-hydroxy-hexanoic acid ethyl ester (5 g, 31 mmol), N-bromosuccinimide (12 g, 67 mmol) and catalytic AIBN in anhydrous CCl4 (60 mL) is refluxed. After heating for about 20 minutes, the reaction initiates with evolution of a red-brown gas. After refluxing 4 hours, the resulting mixture is filtered and the filtrate evaporated at reduced pressure to obtain 3-bromo-2-oxo-hexanoic acid ethyl ester as a dark liquid. Step 2. Preparation of 3-(1-propyl)-imidazolo[1,2-a]pyridine-2-carboxylate
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][Br:19])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][Br:19])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(C)(CBr)COc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(C)CBr)ncn1
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.16 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.56 g of 4-chloro-6-(3-bromo-2,2-dimethylpropyloxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.54 g of 4-(2-butynyloxy)-6-(3-bromo-2,2-dimethylpropyloxy)pyrimidine (the present compound (13)).