Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]([C:7]1[C:12]([CH2:13]O)=[CH:11][C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][N:8]=1)=[O:6])(C)C.[CH3:23][O:24][C:25](=[O:38])[CH2:26][NH:27]S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>>[CH3:23][O:24][C:25]([C:26]1[C:5]([OH:6])=[C:7]2[C:12]([CH:11]=[C:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:9]=[N:8]2)=[CH:13][N:27]=1)=[O:38]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)OC(=O)c1ncc(Cc2ccc(F)cc2)cc1CO
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1ncc2cc(Cc3ccc(F)cc3)cnc2c1O
Yield: 83 %

Procedure:
After subjecting the above Compound 5 (59.0 g, 195 mmol) to Mitsunobu reaction with N-tosylglycine methyl ester according to the method described in Document (WO02/30930), ring-closure was caused with 1M sodium methoxide, to give 3-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester 6 (50.3 g) in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:12]=1.[CH2:27]=O>C(Cl)(Cl)Cl>[C:20]1([CH2:19][N:16]2[CH2:17][CH2:18][CH:13]([N:11]3[C:12]4[CH:27]=[N:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=5[C:8]=4[NH:9][C:10]3=[O:26])[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1-c1cn(C2CCN(Cc3ccccc3)CC2)c(=O)[nH]1
Reactant: C=O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.67 g (7.66 mmol) of 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one in 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde and refluxed for 3.5 hours. The residue remaining after evaporation of the solvent was taken up in 100 ml of methanol and acidified with methanolic hydrogen chloride solution. After stirring for one hour at room temperature the mixture was poured into 300 ml of saturated sodium hydrogen carbonate solution. The resulting mixture was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was purified by column chromatography over silica gel using FM4 as eluant. From the appropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphous substance were isolated, Rf=0.24 (FM4)
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](OC1CCC(C(=O)O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 64.2 g of ethyl 4-((tert-butyl(diphenyl)silyl)oxy)cyclohexanecarboxylate in 200 ml of methanol and 200 ml of tetrahydrofuran was added 58 ml of 5 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized with 5 M aqueous hydrochloride solution, followed by removal of the methanol and tetrahydrofuran in vacuo, and the resulting residue was extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([NH:13][CH2:10][CH:11]=[CH2:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCN
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: C=CCNC(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of 100 g (0.84 mole) phenylisocyanate in 50 ml of benzene was added dropwise over a period of 30 minutes to a stirring solution of 60 g (1.05 mole) allyl amine in 2 liters of benzene. The mixture was stirred overnight and suction filtered yielding 120 g (95% yield) of 1-phenyl-3-allyl urea with a melting point of 112°-113°. This material was also characterized by IR and nmr analysis.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[C:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(O)(C)C>C(O)C>[OH:1][NH:2][C:3](=[O:24])[C@@:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: CC(O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Solvent: CCO
Solvent: CC(C)O
Product: C[C@@](O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Yield: 41.8 %

Procedure:
A solution of N,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide (20 g) in ethanol (1500 mL) was sequentially injected in 12 mL portions onto a Prochrom® column (50 mm I.D., 36 mm bed length) packed with Chiralpak® AD. The mobile phase used was 30% isopropyl alcohol/70% heptane. Fractions were collected automatically and pooled. The first eluting peak was collected and the appropriate fractions were combined to provide the title compound (8.351 g). HPLC purity: 100%.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:31]([CH3:33])[CH3:32]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CC(C)Br
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 373 and 2-bromopropane, white powdery N-[2-(3-difluoromethoxy-4-isopropoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.[CH2:13]([N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:22]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:21][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[NH2:12])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN(Cc1ccccc1)Cc1ccccc1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(F)c(F)cc1C(=O)NN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 157.5 %

Procedure:
4,5-Difluoroanthranilic acid (4.73 g, 27.3 mmol) and N,N-dibenzylhydrazine (8.69 g, 42 mmol) are combined in 200 mL of methylene chloride. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (7.85 g, 41 mmol) is then added to this solution, and the mixture is stirred for 18 hours at 25° C., The solution is washed with saturated NaHCO3, brine, and dried over magnesium sulfate. The solution is concentrated to give 15.8 g of a dark oil and purified via chromatography (SiO2, CHCl3) to give 3.4 g of the title compound as a solid. MS CI: m/z 368 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:16]=[C:24]([NH2:25])[CH:23]=[C:22]([NH2:26])[N:17]=2)=[N:6]1
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2ccccc2F)n1
Reactant: N#CCC#N
Solvent: CCO
Product: Nc1cc(N)nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)n1
Temperature: 110 °C
Yield: 31.1 %

Procedure:
To a solution of 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (50 mg, 0.18 mmol) in ethanol (2 mL) was added malononitrile (35 mg, 0.53 mmol). After heating the solution to 110° C. for 6 hours, the solvent was removed in vacuo to give the crude product as a red oil. Purification by silica gel chromatography (0-10% methanol in dichloromethane) gave 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,6-diamine (I-103, 20 mg, 0.056 mmol, 32% yield) as a pink solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, 1H), 7.31 (s, 1H), 7.19-7.14 (m, 1H), 7.01-6.96 (m, 1H), 6.92 (t, 1H), 6.74-6.71 (m, 1H), 6.58 (d, 1H), 5.90 (s, 2H), 5.57 (s, 1H), 5.03 (br s, 4H).
Reaction SMILES: C(O)(=O)C.[Si]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]2([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])[O:21][C:15]2([CH3:27])[CH2:14]1)(C(C)(C)C)(C)C>[Zn].C(Cl)(Cl)Cl>[OH:21][C:15]1([CH3:27])[CH2:14][CH:13]([OH:12])[CH2:18][C:17]([CH3:19])([CH3:20])[CH:16]1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)C=CC12OC1(C)CC(O[Si](C)(C)C(C)(C)C)CC2(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CC1C(C)(C)CC(O)CC1(C)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
To 50 ml of a glacial acetic acid solution containing 600 mg of 4-[4-(t-butyldimethylsilyl)oxy-1,2-epoxy-2,6,6-trimethylcyclohexyl]but-3-en-2-one was added 8.9 g of a zinc powder at room temperature, and the mixture was vigorously stirred for 5 hours while maintaining the reaction temperature at about 40° C. To the reaction mixture was added 120 ml of chloroform, followed by stirring vigorously. Any insoluble matter was separated by filtration, and the filtrate was washed successively with water, a 5% aqueous solution of sodium hydrogen carbonate and water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. Purification of the resiude by silica gel chromatography gave 241 mg (yield: 55%) of 4-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)but-3-en-2-one.
Reaction SMILES: [NH+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1.[OH-].[Na+]>C(O)(C)C>[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc[nH+]cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: C(=Cc1ccncc1)c1ccccc1
Reaction time: 2 h

Procedure:
To 67.5 parts of the 4-picolinium quaternary salt as in Example 13 but without the acid salt was added 100 parts isopropanol, 32.5 parts benzaldehyde, and one part piperidine. The resulting solution was boiled at reflux two hours, 100 parts 40% sodium hydroxide added, and the heating continued for two hours. The cooled mixture was extracted with chloroform, and the organic phase evaporated to dryness to yield a residue that was recrystallized from methanol-water to give 21 parts 4-styrylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH2:21]([O:28][CH2:29][C:30](Cl)=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C1COCC1>[CH2:21]([O:28][CH2:29][C:30]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)COCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)COCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.10 g, 4 mmol) in THF (30 ml) was added benzyloxyacetyl chloride (1.26 ml, 8 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo and the residue was slurried in diethyl ether (30 ml), filtered, recrystallized from a minimal amount of acetic acid, slurried in ethyl acetate (15 ml), and filtered to give 1.35 g (80%) of product: mp 204–206° C.; 1H NMR (DMSO-d6) d 11.20 (s, 1H), 10.40 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.50–7.28 (m, 5H), 5.17 (dd, J=5.0 and 12.5 Hz, 1H), 4.72 (s, 2H), 4.21 (s, 2H), 2.99–2.85 (m, 1H), 2.67–2.51 (m, 2H), 2.12–2.08 (m, 1H); 13C NMR (DMSO-d6) d 172.78, 169.78, 169.01, 168.27, 166.67, 137.04, 136.52, 135.93, 131.29, 128.36, 127.82, 124.40, 118.38, 116.08, 72.78, 69.23, 48.97, 30.92, 21.98; Anal. Calcd. For C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.77; H, 4.54; N, 9.82.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([CH3:14])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[K+]>O.CO>[CH2:18]([O:17][C:15]([C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:5]=1[CH3:14])=[O:16])[CH3:19]
Reactant: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1[nH]c(C)c(CCC(=O)O)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a suspension of 10 g (38.9 mmol) ethyl 2,4-dimethyl-5-(ethoxycarbonyl)-3-pyrrolepropionate (commercially available) in a mixture of water (250 mL) and methanol (MeOH) (50 mL) was added 3.0 g of KOH in 50 mL of water. The mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled and the methanol was stripped from the mixture under vacuum. The remaining solution was filtered and the filtrate was then acidified with 6N hydrochloric acid to pH 3. The precipitate which formed was collected by filtration, washed with a 2:1 mixture of water and ethanol and dried under vacuum to give 7.5 g of 4-(2-carboxy-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])=[N+:2]=[N-:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13]>C1(C)C=CC=CC=1>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N:1]1[CH:13]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccccc2F)nn1
Temperature: 100 °C
Reaction time: 13 h
Yield: 6.5 %

Procedure:
1-Azido-2-fluorobenzene (1.0 g) and ethyl propiolate (2.2 g) were dissolved in toluene (12 ml) and the mixture was stirred at 100° C. for 13 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-80:20) was concentrated under reduced pressure to give the object product (111 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N:15]#[C:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:11]([O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]2[N:7]([C:16]([NH2:15])=[N:14][N:13]=2)[N:8]=1)[CH3:12]
Reactant: N#CBr
Reactant: CCOc1cc(NN)nnc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOc1cc2nnc(N)n2nc1OCC
Reaction time: 8 h
Yield: 63.9 %

Procedure:
(5,6-Diethoxy-pyridazin-3-yl)hydrazine (W3.120; 50 mg) was initially charged in a mixture of ethanol (3.5 ml) and water (0.75 ml) at RT while stirring. Thereafter, cyanogen bromide (55 mg, dissolved in 0.75 ml of ethanol and 0.15 ml of water) was cautiously added dropwise. After stirring for 7 h, the mixture was left to stand overnight. Thereafter, a further 2 equivalents of cyanogen bromide, dissolved in 0.75 ml of ethanol and 0.15 ml of water, were added and the mixture was stirred further at RT for 2 h and then at 55° C. for 8 h. After cooling, the solvent was drawn off and the residue was admixed with water. After it had been alkalized with saturated potassium carbonate solution, it was extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 36 mg of the title compound were obtained. LC-MS rt: 0.54 min [M+H]+: 224.2 (met. b)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li]CCCC.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.Cl>>[B:13]([OH:18])([OH:14])[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccsc1Br
Agent: Cl
Agent: [Li]CCCC
Product: Cc1ccsc1B(O)O
Yield: 93 %

Procedure:
2-Bromo-3-methylthiophene was treated with n-BuLi (1.6 M in hexanes, 38.8 mL, 62.1 mmol), triisopropyl borate (15.1 mL, 65.4 mmol) and HCl(aq) (2.7 N, 52.5 mL) as for 1 to give the title compound 5 (7.2 g, 93% yield) as a brown solid: 1H NMR (CD3OD) δ 7.27 (d, J=5.5 Hz, 1H), 6.80 (d, J=5.5 Hz, 1H), 2.16 (s, 3H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[C:20](Br)Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:23](Cl)(=[O:26])[O:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]#[C:20][C:23]([O:24][CH3:25])=[O:26])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.57N hexane solution, 3.11 ml) was added dropwise to a solution with 1-(tert-butoxycarbonyl)-4-(2,2-dibromovinyl)piperidine (WO9806720) (900 mg) dissolved in tetrahydrofuran (16 ml) at −78° C., and the mixture was stirred for 1 hour. Methyl chlorocarbonate (377 μl) was added to the reaction mixture to heat the mixture to room temperature in 1 hour. Diethyl ether (30 ml) and a saturated aqueous solution (50 ml) of ammonium chloride were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (634 mg) as a colorless transparent oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:29](=[O:30])[CH2:28][CH:27]([CH2:31]OS(C)(=O)=O)[CH2:26]1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:31][CH:27]2[CH2:28][C:29](=[O:30])[N:25]([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[CH2:26]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CS(=O)(=O)OCC1CC(=O)N(c2ccc(F)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Temperature: 57.5 °C
Yield: 88.3 %

Procedure:
A mixture of 1H-Pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.713 mmol), potassium carbonate (0.019 g, 1.42 mmol), Methanesulfonic acid 1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.32 g, 1.07 mmol) were taken in DMF (2 ml). The reaction mixture was heated at 55-60° C. for 20 hour. The mixture was cooled to room temperature and then to this reaction mixture water (20 ml) was added and extracted with ethyl acetate (3×25 ml), organic layers were combined and washed with brine (25 ml), dried over Na2SO4 and evaporated to dryness to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.22 g, 91%) as a brownish sticky mass.
Reaction SMILES: C([O:4][CH:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:8]=2[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[N:6]1)(=O)C.CO.[OH-].[Na+]>O1CCCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:9]2[C:10]3[N:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:5]([OH:4])[N:6]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:8]=2[CH:19]=1
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.7 g (9.7 mmole) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol acetate in a mixture of 25 ml of tetrahydrofuran, 50 ml of methanol and 2 ml of 3N sodium hydroxide was stirred at room temperature for 0.5 hr. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue crystallized from a mixture of methylene chloride and ether to give a crude product melting at 186°-188° C. Recrystallization from a mixture of ether and methylene chloride gave the product as cream colored prisms, mp 196°-198° C.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]#[N:2])=[C:6]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:7]=1
Reactant: N#C[Cu]
Reactant: Fc1ccc(Br)c(-n2cccn2)c1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1cccn1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a stirred suspension of CuCN (358 mg, 4.0 mmol, Aldrich) in DMF (2 mL, Sure Seal) was added a solution of 1-(2-Bromo-5-fluoro-phenyl)-1H-pyrazole (964 mg, 4.0 mmol) in DMF (2 mL) and the resulting clear solution was stirred in an oil bath heated at 110° C. under nitrogen for 1.5 h. After cooling, the mixture was concentrated in vacuo and the residue mixed with 14% aqueous NH4OH (10 mL) was stirred at room temperature for 0.5 h. To this was added EtOAc (15 mL) and the mixture stirred for additional 0.5 h. The EtOAc extract was washed with dil. NH4OH and then with brine, dried (Na2SO4), filtered, and concentrated. The residual oil was purified by column chromatography (SiO2, 0-10% EtOAc/CH2Cl2) to obtain 542 mg of the title compound as a white crystalline solid: TLC Rf 0.42 (CH2Cl2); HPLC rt=1.94 min. LC/MS m/z 188 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 6.55 (1H, dd, J=2.6, 1.7 Hz, 9-CH), 7.10-7.13 (1H, m, 5-CH), 7.59 (1H, dd, J=9.5, 2.5 Hz, 3-CH), 7.76 (1H, dd, J=8.7, 5.5 Hz, 6-CH), 7.80 (1H, d, J=−1.2 Hz, 10-CH), 8.25 (1H, d, J=2.7 Hz, 8-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 100.5 (d, J=3.8 Hz, 1-C), 109.1 (9-CH), 111.9 (d, J=27 Hz, 3-CH), 114.9 (d, J=23 Hz, 5-CH), 116.6 (7-CN), 129.5 (8-CH), 136.7 (d, J=10 Hz, 6-CH), 142.8 (10-CH), 144.2 (d, J=12 Hz, 2-C), 165.5 (d, J=258 Hz, 4-CF); HRMS (ESI) calcd for C10H7FN3 (M+H) 189.0576, found 189.0568 (δ-4.5 ppm); UV (MeOH) λ max 224 nm (ε2.54×104), 261 nm (ε1.20×104); Anal. calcd for C10H7FN3: C, 64.16; H, 3.24; N, 22.45; found C, 64.02; H, 3.16; N, 22.68.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH-].[NH4+:14]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH2:14])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60.0 g of 2,3-dichlorobenzenesulfonyl chloride in 500 mL of tetrahydrofuran at 0° C. was added 30 mL of concentrated ammonium hydroxide (30%) dropwise at a rate that maintained the temperature below 15° C. After an additional stirring period of 0.5 hr, the tetrahydrofuran was evaporated under reduced pressure. The resultant solid residue was triturated with 500 mL of water, filtered, and the collected solid washed twice with 100-mL portions of water and dried to yield 52 g of 2,3-dichlorobenzenesulfonamide as a tan solid, m.p. 210°-226° C.; IR (nujol): 3360, 3250, 1370, 1175, 1165 cm-1.