Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)Cl>[Br:17][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][C:4]=1[CH2:8][CH3:9]
Reactant: CCc1cccc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCc1nc(N)ccc1Br
Reaction time: 0.75 h
Yield: 77.6 %

Procedure:
A 0° C. solution of 2-amino-6-ethylpyridine (3.00 g, 24.56 mmol) in CHCl3 (25 mL) was treated portion-wise with NBS (4.37 g, 24.56 mmol) over 30 minutes, stirred for 45 minutes, then concentrated to dryness. The residue was treated with EtOAc, the solids removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-bromo-6-ethylpyridin-2-amine (3.83 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.42 (d, J=8.6 Hz, 1H), 6.20 (d, J=8.7 Hz, 1H), 6.03 (s, 2H), 2.60 (q, J=7.5 Hz, 2H), 1.10 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 203.0 (M+H+).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[N+:47]([C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1)([O-:49])=[O:48]>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:47]([C:50]1[CH:55]=[C:54]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:53]=[CH:52][CH:51]=1)([O-:49])=[O:48]
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(-c3cccc([N+](=O)[O-])c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (35 mg, 0.104 mmol) (Starting Material 1), Et3N (58 μL, 0.415 mmol), tri-o-tolylphosphine (6 mg, 0.020 mmol) (Aldrich), Pd(OAc)2 (2 mg, 0.009 mmol) (Aldrich), and 3-nitrophenylboronic acid (26 mg, 0.156 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide was heated at 100° C. for 16 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-4-(3-nitrophenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (24.1 mg, 70%) as an orange solid (mp 197-199° C.).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:46])([CH2:44][CH3:45])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[F:31])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:46])([CH2:44][CH3:45])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[F:31])[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(F)c2ccc(-c3ccccn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(F)c2ccc(-c3ccccn3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (4 mL, 1 mmol) was added to an ambient temperature solution of 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-fluoroethyl}phenyl)pyridine (240 mg, 0.4 mmol) in methanol (20 mL). After stirring at ambient temperature for 3 h, volatiles were removed in vacuo. The residue was partitioned between 1 N hydrochloric acid and diethyl ether. The aqueous phase was washed with diethyl ether, basified with saturated aqueous sodium carbonate and extracted with diethyl ether and ethyl acetate. The combined extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. High pressure liquid chromatography (Chiralcel OJ column) eluting with 15% ethanol/hexane afforded the separate enantiomers. (M+H) found 352.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]2[S:19][C:20]3[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][C:25]=3[C:12]=12>>[C:17]([C:16]1[C:11]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[C:12]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C:20]=3[S:19][C:13]2=[N:14][CH:15]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 3,4-dichloroaniline (116 mg, 0.72 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (250 mg, 0.72 mmol) from Example 53A to yield 207 mg (61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([N:21]([S:28](Cl)(=[O:30])=[O:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH2:14]([N:21]([S:28]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:29])=[O:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCOCC1
Yield: 6 %

Procedure:
A solution of morpholine (1.05 ml, 12 mmol) and triethylamine (1.84 ml, 12 mmol) in methylene chloride (10 ml) was added to a solution of ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate (2.3 g, 8.3 mmol), [prepared as described in Step 1 above], in methylene chloride (30 ml) at 0° C. The reaction mixture was slowly allowed to warm to RT and after 6 h 1M HCl was added. The product was extracted into methylene chloride, washed with brine, and dried over MgSO4. The organics were removed in vacuo and the crude product was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate as a colorless oil (6%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH2:38])=[O:36])=[CH:30][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH:38][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:20])=[O:36])=[CH:30][CH:29]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NN)cc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)cc1
Yield: 74.6 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(4-(2-hydrazinyl-2-oxoethyl)phenyl)carbamate (682.6 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6), 550.8 mg of the title compound was afforded (yield 74.6%).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]1[C:52]2[C:47](=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=2)[CH:46]=[C:45]([C:54]2[CH:55]=[C:56]([NH:61]/[C:62](/[NH2:65])=[N:63]/O)[CH:57]=[CH:58][C:59]=2[CH3:60])[C:44]1=[O:66]>CN(C=O)C>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]1[O:6][N:63]=[C:62]([NH:61][C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([C:45]3[C:44](=[O:66])[N:43]([CH3:42])[C:52]4[C:47]([CH:46]=3)=[CH:48][N:49]=[C:50]([CH3:53])[CH:51]=4)[CH:55]=2)[N:65]=1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)(O)CC(=O)O
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
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(CC(C)(C)O)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-hydroxy-3-methylbutanoic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(2-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A56). MS m/z 420.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCc1ccccc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCc1ccccc1
Yield: 71.4 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenylamine (0.028 g, 0.07 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 66 (0.025 g, 0.05 mmol, 66%) as a solid film. LCMS m/z (%)=525 (M+H79Br35Cl, 85), 527 (M+H81Br35Cl, 100), 529 (M+H81Br37Cl, 31). 1H NMR (400 MHz, acetone-d6) δ: 8.34 (s, 1H), 8.26 (s, 1H), 7.65 (dd, J=2.7, 8.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.53 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.16-7.31 (m, 5H), 7.09-7.16 (m, 3H), 4.11-4.30 (m, 2H), 3.51 (s, 3H), 2.86-3.06 (m, 2H).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:33]=[C:34](I)[CH:35]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:27][O:28][C:29]([C:31]1[N:32]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH:33]=[C:34]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=2[O:8][CH3:7])[CH:35]=1)=[O:30]
Reactant: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)cn1S(=O)(=O)c1ccc(C)cc1
Yield: 48.3 %

Procedure:
To a solution of 15 mL of 1,4-dioxane and 5 mL of water was added 2-(2-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (2.05 g, 5.5 mmol) followed by 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57e (2.03 g, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (144 mg, 0.125 mmol). Upon completion of the addition, the reaction mixture was reacted at 80° C. for 30 minutes under microwave. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was diluted with 20 mL of water. After mixing well, the mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-1-(p-tolylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, yield 48%) as a grey solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:26]=[CH:25][C:21]4[N:22]=[CH:23][NH:24][C:20]=4[CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34]([C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[N:22]1[C:21]2[CH:25]=[CH:26][C:18]([NH:17][C:10]3[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]5[CH:45]=[CH:46][C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:39][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)[N:9]=3)=[CH:19][C:20]=2[NH:24][CH:23]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccc4nc[nH]c4c3)n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc5nc[nH]c5c4)n3)c2)cc1
Temperature: 0 °C

Procedure:
After dissolving 0.34 g (1 mmole) [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(3H-benzoimidazol-5-yl)-amine in 20 mL anhydrous THF, 3 equivalents of triethylamine are added and the reaction solution is cooled to 0° C. A solution of 0.2 g of 4-tert-butyl-benzoyl chloride (1 mmole) in 5 mL THF is added dropwise to the 0° C. reaction solution under N2. The ice bath is removed and the reaction is allowed to warm slowly to rt for 1 hr. Diethyl ether is then added slowly to the reaction solution and the resulting solid filtered and washed with diethyl ether to provide pure N-{3-[8-(3H-benzoimidazol-5-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-4-tert-butyl-benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.Cl(O)(=O)(=O)=O>O>[C:24]([O:18][C:17](=[O:19])[C@H:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[NH2:16])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)(C)C
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Nδ -(Benzyloxycarbonyl)-L-ornithine tert-butyl ester was prepared according to a general published procedure (Bodanszky, M.; Bodanszky, A.; The Practice of Peptide Synthesis; Spring Verlag: New York, 1984). Specifically, Nδ -(benzyloxycarbonyl)-L-ornithine (10.0 gm, 37.6 mmol, Sigma Chemicals, Inc.) was mixed with tert-butyl acetate (564 ml) and perchloric acid (5.91 ml, 69-72% aqueous solution) at room temperature. The reaction mixture became homogenous after 15 minutes and was stirred at room temperature for 2 days. Water (300 ml) was added to the reaction mixture, and the two layers obtained were separated. The organic layer was extracted twice (2×200 ml) with water, and the combined aqueous layers were adjusted to pH 9.5-10.0 with 50% NaOH. The aqueous layer was then filtered to remove a small amount of insoluble material, and the filtrate was extracted with ethyl acetate (3×300 ml). The combined ethyl acetate extracts were dried over MgSO4 and were concentrated by rotary evaporation at reduced pressure to yield 7.5 g of Nδ -(benzyloxycarbonyl)-L-ornithine tert-butyl ester as an oil (65% yield). 1H NMR (DCCl3) δ 1.44 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 3.31 (t,1H), 5.09 (s,2H and s,1H broad), 7.35 (s,5H) .
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(OC(C)C)(C)C>[CH:9](=[N:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(C)OC(C)C
Solvent: O
Product: O[C@@H]1CCCC[C@H]1N=Cc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a reflux condenser and a Dean-Stark trap, 6.91 g of racemic trans-2-aminocyclohexanol (60 mmol) obtained according to (b) were dissolved under argon in 70 ml of diisopropyl ether and 6.1 ml of benzaldehyde (60 mmol) were added to the solution which was refluxed under argon at 110° C. during 50 min until about 1 ml of water separated. The solvent was removed in a rotary evaporator (45° C./250-10 mbar) to obtain 12.11 g of white-beige crystals of racemic trans-2-(benzylidenamino)-cyclohexanol, m.p. 86° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[N:6][CH:7]=1.[Cl:16][C:17]([Cl:22])([Cl:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][C:17]([Cl:22])([Cl:21])[C:18]([C:14]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:19]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cnc(C(=O)Cn2cccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(C(=O)Cn2cccc2C(=O)C(Cl)(Cl)Cl)cn1
Reaction time: 8 h

Procedure:
To a chilled (0° C.) solution of 1-(5-methylpyrazin-2-yl)-2-(1H-pyrrol-1-yl)ethanone (318 mg, 1.58 mmol) in CH2Cl2 (21 mL) was added 2,2,2-trichloroacetyl chloride (400 μL, 3.56 mmol). The solution was allowed at room temperature and stirred until complete (overnight, monitored by LCMS). A chilled saturated solution of NaHCO3(15 mL) was then added and the mixture extracted with CH2Cl2 (3×15 mL). The organic were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that is purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 1 CV hexane, 0-50% EtOAc in hexanes 10 CV; 50-100% 3CV). The compound 2,2,2-Trichloro-1-{1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}ethanone was isolated as a crystalline solid (260 mg, yield 38%). 1H-NMR (400 MHz, CDCl3): δ 2.70 (s, 3H), 5.91 (2H, s), 6.45 (dd, 1H, J 4.4, 2.5, Hz), 7.02 (dd, 1H, J 2.4, 1.6 Hz), 7.64 (dd, 1H, J 4.4, 1.5 Hz), 8.53-8.55 (m, 1H), 9.15 (d, 1H, J 1.3 Hz).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.CCOC(C)=O.[Pd]>[OH:8][C:9]1[C:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(CCCc2ncccc2O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.2 %

Procedure:
Methyl 4-[3-(3-benzyloxy-2-pyridyl)prop-2-enyl]benzoate (1.5 g, 4.2 mmol) was dissolved in ethanol (5 ml) and EtOAc (15 ml), treated with 10% palladium on carbon (0.15 g) and placed under a hydrogen atmosphere. The mixture was stirred at ambient temperature for 10 hours and filtered and evaporated to give methyl 4-[3-(3-hydroxy-2-pyridyl)propyl]benzoate as a yellow oil (0.88 g, 77%).
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].C([Li])CCC.[CH3:21][N:22]=[C:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:6]1[CH2:5][CH2:4][C:3](=[O:15])[N:22]([CH3:21])[C:23]1=[O:24]
Reactant: COC(=O)CCNc1ccc(Cl)cc1Cl
Reactant: CN=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CCN(c2ccc(Cl)cc2Cl)C1=O
Reaction time: 1 h
Yield: 16.1 %

Procedure:
At first, 7.44 g (0.03 moles) of N-(2,4-dichlorophenyl)-β-alanine methyl ester was dissolved in 150 ml of tetrahydrofuran (THF), and 19.2 ml (0.03 moles) of n-butyl lithium was added thereto at -78° C. Several minutes thereafter, 5.4 ml (0.045 moles) of methyl isocyanate was added thereto. The mixture was stirred at the same temperature for one hour, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and recrystallized from toluene, whereby 1.32 g of the desired compound was obtained as colorless prism crystals having a melting point of 154°-157° C. (yield: 16.1%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[OH:16].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:13])([CH3:14])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:28][CH2:27][CH2:26][CH2:25][S:24][C:21]1[CH:20]=[CH:19][C:18]([CH3:17])=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)c(Cl)c21
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5,7-dichloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[N:28]([CH3:29])[N:27]=[CH:26][C:25]=1[C:30]#[N:31]>ClCCl.CN(C)C=O>[C:30]([C:25]1[CH:26]=[N:27][N:28]([CH3:29])[C:24]=1[NH:23][C:12]([C:11]1[C:5]2[S:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=2[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1)=[O:14])#[N:31]
Reactant: Cn1ncc(C#N)c1N
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C#N)cnn3C)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a suspension of 2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (0.1 g) in dichloromethane (10 ml) was added oxalyl chloride (1.0 ml) and dimethylformamide (1 drop). The reaction was stirred at room temperature for 16 hrs, and then the solvent was removed in vacuo to yield a brown solid residue. 5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (0.1 g) was taken up in dichloromethane (10 ml) and sodium hexamethyldisilylamine (1.0M in tetrahydrofuran, 0.84 ml) was added. After 5 minutes the acid chloride was added and the reaction stirred at room temperature for 16 hrs. The solvent was removed in vacuo and the product purified by flash chromatography (eluent 50% ethyl acetatethexane-75% ethyl acetate/hexane) to yield the title compound as an off-white solid (0.088 g). TLC Rf 0.13 (50% ethyl acetate/hexane); Mpt 190-191° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([C:31]2[N:39]3[C:34]([CH:35]=[N:36][C:37](O)=[N:38]3)=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[N:15]1[CH:16]=[C:17]([NH:20][C:37]2[N:36]=[CH:35][C:34]3=[CH:33][CH:32]=[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=4)[N:39]3[N:38]=2)[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)nc4)nn23)c1

Procedure:
This example was prepared by using 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (WO2006/047277) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.9 (s, 1H), 9.1 (s, 1H), 8.8 (s, 1H), 8.7 (s, 1H), 8.6 (brs, 1H), 8.4 (d, J=7.9 Hz, 2H), 8.2 (d, J=8.9 Hz, 1H), 8 (d, J=7.9 Hz, 1H), 7.8 (t, 1H), 7.3 (m, 2H), 7 (d, J=4.4 Hz, 1H), 3.4 (m, 2H), 3.36 (s, 3H), 3.0 (m, 3H), 2.0 (m, 2H), 1.85 (m, 2H); LC/MS (ESI+): 449 (M+H).