Azzindani/Open_Reaction_Data huggingface dataset:
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][C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:30]3[O:29][N:28]=[C:27]([CH3:26])[CH:31]=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: Cc1cc(N)on1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)on1
Temperature: 150 °C
Yield: 25.4 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 292 mol), 3-methylisoxazol-5-amine (43.0 mg, 439 mol), xantphos (50.8 mg, 87.7 mol), Pd2(dba)3 (26.8 mg, 29.2 mol) and cesium carbonate (191 mg, 585 mol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 20-75% ethyl acetate in hexanes) to give N-tert-butyl-2-(3-methylisoxazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 74.2 mol, 25.4%) as a yellow solid. (EI/CI) m/z: 455.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Na].Br[C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Yield: 89.6 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (35 g, 0.23 mol), sodium-4-bromobenzene-sulfonate (50 g, 0.19 mol) and Na2CO3 (200 g) were taken in toluene (1000 ml) and water (500 ml). To this was added Pd(PPh3)4 (11 g, 0.011 mol) and the reaction mixture was refluxed for 12 h under N2 atmosphere. The reaction mixture was cooled, filtered off the solid residue, washed with toluene and acidified with 6N HCl. The solid precipitate was filtered and dried to give 4′-methoxy[1,1′-biphenyl]-4-sulfonic acid (45 g, 88%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].C([O:35][C:36](=[O:39])[CH2:37]Br)C>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:8]([C:7]1[C:6](=[O:10])[NH:5][C:4]2[S:11][CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:37][C:36]([OH:39])=[O:35])=[CH:18][CH:19]=3)[C:3]=2[C:2]=1[OH:1])#[N:9]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4O)cc3)csc2[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4OCC(=O)O)cc3)csc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
To solution of 4-hydroxy-3-(2′-hydroxy-1,1′-biphenyl-4-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.090 g, 0.25 mmol) in acetone (20 mL) was added potassium carbonate (0.14 g, 1 mmol) and tetrabutyl-ammonium iodide (0.005 g, 0.5 mmol) at room temperature. After stirring for 30 min, bromo-acetic acid ethyl ester (0.083 g, 0.5 mmol) was then added into the reaction mixture and stirred for 16 h. The solvent was removed in vacuo, diluted with water (15 mL), extracted with ethyl acetate (3×30 mL), organics extracts washed with brine (15 mL), dried (Na2SO4), concentrated and purified on a RP-HPLC system. The title compound was one of the three reaction products that were purified. MS (ESI) m/e 416.9 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 12.44 (br s, 1H), 7.57 (d, J=7.98, 2H), 7.46 (d, J=8.29, 2H), 7.36–7.30 (m, 2H), 7.08–6.98 (m, 3H), 4.74 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])([OH:3])=O.Cl.[CH3:22][NH:23][CH3:24].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:22][N:23]([CH3:24])[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])=[O:3]
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Reactant: CNC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#CCn1c(-c2ccccc2)nc(C(=O)N(C)C)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.7 %

Procedure:
To a stirred solution of 0.87 g (3.2 mmol) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone, 0.32 g (3.9 mmol) of dimethylamine hydrochloride and 2 mL of pyridine in 10 mL of THF was added 0.74 g (3.6 mmol) of solid N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 4 days and filtered to remove insoluble material. The filtrate was diluted with 150 mL of ethyl acetate, washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate and dried over MgSO4. Removal of the solvent left 0.40 g of crude product which was purified by flash chromatography on a 30 g column of silica gel, eluted with 60, 80 and 100% ethyl acetate in hexanes to furnish 0.30 g (32%) of 6-dimethylaminocarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 19), mp 137°-140° C. 1H-NMR (CDCl3) δ 2.15(3H,s), 2.40(1H,t), 3.00(3H,s), 3.10(3H,s), 4.65(2H,d), 7.55(3H,m), 7.70(2H,m).
Reaction SMILES: [CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10](Br)[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[SH:26].[OH-].[K+]>N1C=CC=CC=1.O>[CH2:1]1[O:17][C:4]2([C:12]3[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([S:26][C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])[CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C1(CC2)OCCO1
Reactant: Fc1ccc(S)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc2c(cc1Sc1ccc(F)cc1F)C1(CC2)OCCO1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a mixture of 5-nitro-6-bromo-1-indanone ethylene ketal (600 mg, 2.0 mmol) and 2,4-difluorothiophenol (F. Klages and K. Bott Chem. Ber. 97,735 (1964)) (440 mg, 3.0 mmol) in pyridine (4.0 mL) was added a solution of 8M aqueous potassium hydroxide (375 μL, 3.0 mmol) at room temperature. The mixture was stirred for 2 h, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed successively with 1M aqueous NaOH (2x),0.5M aqueous HCl (1x), brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and eluted with toluene: ethyl acetate (10:1) afforded the title compound (590 mg, 81%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[N:10][C:11]([O:16][CH2:17][C:18]#[N:19])=[C:12]([CH:15]=2)[C:13]#[N:14])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[NH2:14][C:13]1[C:12]2[C:11](=[N:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:15]=2)[O:16][C:17]=1[C:18]#[N:19]
Reactant: N#CCOc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from Step A (0.132 g; 0.319 mmol) in TB (3 mL) cooled to 0° C. was treated with 1 M solution of lithium bis(trimethylsilyl)amide in THF (701 μL; 0.701 mmol) and stirred at 0° C. under nitrogen for 15 minutes. The reaction mixture was warmed to room temperature and then stirred for an additional 15 minutes. The reaction mixture was partitioned between EtOAc and 10% NaHSO4 aqueous solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 413.9 (M+1), 415.9 (M+3); Rt=4.50 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: BrCCCCSc1ccccc1
Product: O=C1CCc2c(cccc2OCCCCSc2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylmercapto-butyl bromide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2[nH]ncc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 1H-indazole-5-carboxylic acid (400 mg, 2.47 mmol) in N,N-dimethylformamide (8 ml) were added 1-benzylpiperazine (435 mg 2.47 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (565 mg, 2.96 mmol), hydroxybenzotriazole (367 mg, 2.72 mmol) and triethylamine (0.56 ml, 3.95 mmol), and the resulting mixture was stirred overnight at room temperature. Then, a 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with chloroform. A 1N-aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with chloroform. The combined organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 5-[(4-benzyl-1-piperazinyl)carbonyl]-1H-indazole (624 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To 1-(4-fluorophenyl)-1H-indazole-5-carbaldehyde (240 mg, 1.0 mmol) in anhydrous THF (5 mL) was added benzylmagnesium bromide (19% solution in THF, 3 mL, 3 mmol) dropwise at rt under argon. The reaction mixture was stirred at rt for 30 min and quenched by the slow addition of saturated aqueous ammonium chloride solution (5 mL). The mixture was extracted with ethyl acetate (2×4 mL). The combined ethyl acetate extracts were dried (Na2SO4), concentrated and purified by silica gel flash chromatography to give 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylethanol (330 mg, 1.0 mmol, 100% yield) as a yellow oil.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[CH:20].ClC1C=CC2NC(=O)C3C=CC=CC=3NC=2C=1>>[CH2:20]([N:8]1[C:7](=[O:16])[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Agent: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Product: C#CCN1C(=O)c2ccccc2Oc2ccccc21

Procedure:
Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-one and 3-bromoprop-1-yne the title compound 85 was obtained (1.58 g, 89%) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 7.76 (ddd, J=7.5, 1.7, 0.4 Hz, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.61 (ddd, J=8.2, 7.2, 1.8 Hz, 1H), 7.41 (dd, J=7.8, 1.6 Hz, 1H), 7.37 (ddd, J=8.2, 1.0, 0.4 Hz, 1H), 7.34-7.24 (m, 3H), 4.83 (d, J=2.3 Hz, 2H), 3.31 (t, J=2.3 Hz, 1H). MS (m/z): 250.0 (M+H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[N+:24]([C:18]1[CH:19]=[C:20]([NH:21][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)[CH:22]=[CH:23][C:17]=1[CH3:16])([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of 3-morpholinobenzoyl chloride (0.24 g) in methylene chloride (5 ml) was added to a stirred mixture of 4-methyl-3-nitroaniline (0.15 g), pyridine (0.24 ml) and methylene chloride (10 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and evaporated. The residual solid was triturated under diethyl ether and the resultant solid was isolated and dried to give N-(3-nitro-4-methylphenyl)-3-morpholinobenzamide (0.28 g); NMR Spectrum: (DMSOd6) 3.2 (t, 4H), 3.3 (s, 3H), 3.78 (t, 4H), 7.19 (s, 1H), 7.4 (m, 2H), 7.47 (d, 2H), 8.0 (d, 1H), 8.83 (s, 1H), 10.23 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:33])[CH:20]4[NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:17]=3[C:34]([O:36]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:35])=[CH:14][N:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH2:23][S:22][CH:21]4[N:18]([C:19](=[O:33])[CH:20]4[NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[C:17]=3[C:34]([OH:36])=[O:35])=[CH:14][N:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1
Solvent: COc1ccccc1
Solvent: O=CO
Product: CC(=O)Nc1ccc(-c2ncc(C3=C(C(=O)O)N4C(=O)C(NC(=O)Cc5cccs5)C4SC3)s2)cc1
Yield: 86.3 %

Procedure:
Following the working method described in Example 4, 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-benzhydryloxycarbonyl-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.5 g) is treated with formic acid (25 cc) and anisole (5 cc) at 50° C. for 20 minutes. 3-[2-(4-acetamido-phenyl)-thiazol-5-yl]-2-carboxy-8-oxo-7-[(thien-2-yl)-acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.99 g) is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2].CN(C=O)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>O>[N:74]1([C:30]([C:29]2[CH:28]=[C:27]([CH:4]([N:5]3[CH:9]=[C:8]([C:10]4[C:11]5[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[C:12]=5[N:13]=[CH:14][N:15]=4)[CH:7]=[N:6]3)[CH2:3][C:1]#[N:2])[CH:35]=[CH:34][CH:33]=2)=[O:31])[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc(C(=O)O)c4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc(C(=O)N5CCOCC5)c4)c3)ncnc21
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (36 mg, 0.000095 mol) and DIPEA (30 μL, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water was added and the product was extracted with ethyl acetate. The combined organic extracts were washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3-(morpholine-4-carbonyl)phenyl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]propanenitrile as a crude (40 mg, 88%) product. MS (ES): 558 (M+1).
Reaction SMILES: Br.[CH:2]1([CH2:8][C@@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>>[CH:2]1([CH2:8][C@@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CC1CCCCC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](CC3CCCCC3)C2)o[nH]1
Reaction time: 8 h
Yield: 69 %

Procedure:
HBr (33% in acetic acid) (7 mL) was added to a reaction flask containing (2R,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.11 g, 0.34 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated. Purification using preparative HPLC (pH=11, small column, sample dissolved in methanol/water (50/50), gradient 0-40, 20 minutes) gave the title compound (62 mg, yield 69%). 1H NMR (600 MHz, cd3od) δ 0.94 (s, 2H), 1.18 (s, 1H), 1.27 (s, 2H), 1.35-1.55 (m, 3H), 1.57-1.80 (m, 6H), 2.01 (s, 1H), 2.13 (s, 1H), 2.24 (s, 1H), 3.09 (s, 1H), 3.22 (s, 3H), 5.53 (s, 1H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([OH:67])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8].[N+](=[CH2:82])=[N-].C(O)(=O)C>CO>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:79][CH2:78][CH2:77][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([N:38]1[CH2:76][CH2:75][CH2:74][C@H:39]1[C:40]([NH:42][C@H:43]([C:49]([NH:51][C@H:52]([C:57]([N:59]1[CH2:73][CH2:72][CH2:71][C@H:60]1[C:61]([N:63]1[CH2:70][CH2:69][CH2:68][C@H:64]1[C:65]([O:67][CH3:82])=[O:66])=[O:62])=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH2:44][CH2:45][C:46](=[O:48])[NH2:47])=[O:41])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OC
Reaction time: 7 h

Procedure:
Pyroglutamyl-tryptophyl-prolyl-arginyl-prolyl-glutaminyl-isoleucyl-prolyl-proline (1.6 g) is dissolved in 80 ml of methanol. To this, excess ethereal diazomethane is added and the solution is kept for 7 hours at room temperature. Acetic acid is added to destroy the excess diazomethane and the resulting mixture is concentrated to dryness in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:22][N:23](C)C)[C:14](=O)[CH:15]3[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:27]N>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:22]=[N:23][NH:27][C:14]=2[CH:15]3[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-2-dimethylaminomethylene-4-methyl-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (1 mL) followed by hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-7-methyl-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.72, Method [1], MS (ESI) 352.0 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.47-7.43 (m, 2H), 7.27 (s, 1H), 5.2 (b s, 1H), 4.09 (d, J=4.94 Hz, 1H), 2.89 (q, J=7.14 Hz, 1H), 1.82-1.60 (m, 3H), 1.42-1.34 (m, 3H), 1.19 (d, J=7.14 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 149.9, 140.7, 139.0, 129.6, 128.7, 126.4, 115.6, 55.83, 48.6, 34.1, 31.1, 30.9, 21.8, 15.6 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:21][C:22]1[CH:23]=[C:24]([C@H:29]([NH2:31])[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([C@H:29]([NH:31][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: C[C@@H](N)c1cc(F)cc(F)c1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(C(N[C@H](C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (1a), 4.42 of 4-methoxyphenyl 3-nitrophenyl ketone, 4.42 g of (R)-1-(3,5-difluorophenyl)ethylamine hydrochloride, 11.7 ml of triethylamine, 2.01 ml of titanium tetrachloride, 4.25 g of sodium cyanoborohydride and 1.31 ml of acetic acid were reacted, to obtain 860 mg of the more polar isomer B of the title compound as a yellow oil.