Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:33][N:34]1[C:38]([CH3:39])=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([CH3:49])=[N:35]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:24]([N:17]([C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:37]2[C:36]([CH3:49])=[N:35][N:34]([CH3:33])[C:38]=2[CH3:39])[CH2:12]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)C(=O)N(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(Cc1ccccc1)C(=O)C(C)(C)C)C2
Reaction time: 2 h
Yield: 86 %

Procedure:
(6S)-6-[Benzyl(tert-butylcarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (0.5 g, 1.028 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.350 g, 1.482 mmol) and Pd(PPh3)4 (0.170 g, 0.147 mmol) were added to a solution of K2CO3 (0.30 g, 2.17 mmol) in a mixture of 1,2,-dimethoxyethane (30 mL) and H2O (4 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 2 h. It was allowed to reach room temperature, diluted with AcOEt (300 mL) and filtered through Celite (washing with AcOEt). The organic layer was washed with brine (1×200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (80-100% AcOEt/Hexane) to afford 0.38 g of the coupling product (Rf=0.1 (30% AcOEt/Hexane), viscous yellow oil, 83% yield).
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CO>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]([CH3:12])=[N:31]2)=[CH:26][CH:25]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1=NN(c2ccc(Br)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzoylacetone (3.63 g, 0.0224 mol) and N,N-diisopropylethylamine (2.88 g, 0.0224 mol) in anhydrous methanol (160 mL), 4-bromophenylhydrazine hydrochloride was added and the resulting mixture was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting mixture was partitioned between a 5% solution of citric acid solution in water (200 mL) and ethyl acetate (150 mL). The organic phase was successively washed with water (2×200 mL) and brine (150 mL), dried with magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 1-(4-bromophenyl)-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (4.05 g, 0.0129 mol) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].C(O)C.[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: CC1(C)CC=C(OS(=O)(=O)C(F)(F)F)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: CCO
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-nitrophenylboronic acid (14.2 g, 85.19 mmol) in toluene (250 mL)-ethanol(125 mL) were added trifluoromethanesulfonic acid 4,4-dimethylcyclohex-1-enyl ester (20 g, 77.44 mmol) prepared in Example (1a), tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.87 mmol) and 2N aqueous sodium carbonate (128 mL, 256 mmol). The mixture was stirred at an external temperature of 100° C. for 1 hour and 45 minutes under a nitrogen atmosphere.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:37])=[O:22])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:1][CH3:2])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[CH3:37])=[O:22])=[O:15]
Reactant: Cc1cc(OC2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(NC(=O)c3nc[nH]c3C(=O)Nc3nc4ccccc4[nH]3)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N5-(1H-benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.0465 g, 0.1 mmol) was added, followed by a DMF solution (3.0 ml) of sodium triacetoxyborohydride (0.106 g, 0.5 mmol). The reaction mixture was stir at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) to give N5-1H-benzimidazol-2-yl-N4-{4-[(1-ethylpiperidin-4-yl)oxy]-2-methylphenyl}-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.22 (s, 1H), 7.52 (m, 1H), 7.41 (m, 2H), 7.23 (m, 2H), 6.97 (m, 2H), 4.75 (m, 1H), 3.54 (m, 2H), 3.37 (m, 3H), 3.12 (m, 4H), 2.24 (m, 4H), 1.22 (s, 3H); MS (EI): 488.7 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][CH2:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH:11]=1)[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCN)CCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCCNC(=O)c1ccccc1)CCCc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 10.1 g benzoyl chloride in 15 ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0° and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2 N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title compound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73°-74° after crystallization from methanol/water/ethyl acetate (1:1:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:27]1([O:32][C:33](=[O:47])[C@@H:34]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:37][CH2:36][CH2:35][C@@H:34]([C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:47])[NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCOc1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 4-bromophenol (261 mg, 1.510 mmol) in acetonitrile (2 ml) under nitrogen, was added BEMP (397 μl, 1.373 mmol). The mixture was stirred at 50° C. for 30 minutes before being cooled to room temperature and (S)-5-bromo-2-tert-butoxycarbonylamino-pentanoic acid cyclopentyl ester (500 mg, 1.373 mmol) added as a solution in acetonitrile (2 ml). The reaction was heated at 50° C. for a further 1 hour and then the mixture was analysed by LCMS. The reaction was poured onto 2M Na2CO3 (100 ml) and extracted with EtOAc (2×100 ml). The combined organic layers were washed with 2M Na2CO3 (3×100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to afford a colourless oil. MP-carbonate (1.0 g) was added to a solution of the crude product in dichloromethane (3.4 ml) and the solution was left overnight at room temperature. LCMS indicated complete removal of 4-bromophenol and so the reaction was filtered to remove the MP-carbonate and the resin was washed with DCM (2×50 ml). The filtrate was concentrated to afford the crude product which was purified by column chromatography eluting with 5% EtOAc in iso-hexane. Yield of title compound=435 mg, 0.953 mmol, 69.4% yield. m/z 456 and 458 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[N:30]=[CH:31][C:32](=[O:35])[N:33]([CH3:39])[CH:34]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(-c2cnc(O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cnc(-c2cn(C)c(=O)cn2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
1-(benzoyl)-4-[(4-methoxy-7-(2-hydroxyl-pyrazin-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine (6 mg), MeI (5 mg) and K2CO3 (4 mg) were dissolved in acetone (5 ml). The reaction was stirred for four hours at room temperature. After solid was filtered away, the mother liquid was concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide 3.0 mg of the desired compound, 1-(benzoyl)-4-[(4-methoxy-7-(1-methylpyrazin-2-on-5-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine. MS m/z: (M+H)+ Calc'd for C26H25N6O5: 501.19; found 501.14. HPLC retention time: 1.08 minutes (column G).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:15][C:16]([C:18]1[O:19][C:20]([CH2:23][O:24][CH3:25])=[CH:21][CH:22]=1)=O.Cl>C1COCC1>[CH3:25][O:24][CH2:23][C:20]1[O:19][C:18]([C:16](=[O:15])[CH2:2][C:1]#[N:3])=[CH:22][CH:21]=1
Reactant: COCc1ccc(C(=O)OC)o1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)CC#N)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Following the method of Turner and Jacks (J. Org Chem. 1989, 54, 4229), to a stirred solution of 11.4 ml (216 mmol) acetonitrile in 50 ml dry THF under argon at −78° C. was added dropwise 95.0 ml (95.0 mmol) lithium bis(trimethylsilyl)amide solution (1 M in THF) and stirring continued for 30 minutes, after which a solution of 7.34 g (43.1 mmol) 5-methoxymethyl-furan-2-carboxylic acid methyl ester in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. over 2 hours. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 7.73 g (99%) 3-(5-methoxymethyl-furan-2-yl)-3-oxo-propionitrile as an orange crystalline solid. EI-MS m/e (%): 179 (M+, 23), 148 ([M—OCH3]+, 40), 147 ([M—CH3OH]+, 44), 139 ([M—CH2CN]+, 45), 111 ([M—COCH2CN]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:21][C@@H:20]([CH3:22])[N:11]2[C:12]3[CH:13]=[C:14]([N:36]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)cc3N21
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)cc3N21
Temperature: 80 °C

Procedure:
A mixture of (4R,10aR)-7-bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (3.0 g, 8 mmol), benzophenone imine (1.52 g, 8 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (85 mg, 0.08 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (153 mg, 0.24 mmol) and sodium tert-butylate (1.1 g, 11.4 mmol) in toluene (30 mL) was heated to 80° C. for 3 h. After cooling the mixture was diluted with diethyl ether (300 mL) and filtered through Celite®. The solvents were evaporated and the residue was purified by chromatography on silica gel with ethylacetate/n-hexane (1:4). The title product was isolated as yellowish foam (3.4 g, 89%); ISP-MS: m/e=468.3 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:13][CH:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)CCCCCl
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(Br)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 6-chloro-2-oxohexanoate (2.9 g, 15 mmol) in carbon tetrachloride (30 mL) was added bromine (0.85 mL, 16.5 mmol) and stirred at rt for 1 hour. The reaction mixture was diluted with EtOAc, washed with Na2S2O3 solution, water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to provide the desired product ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) in 95% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.25 (1H, dd), 4.29 (2H, q), 3.71 (2H, t), 2.16 (1H, m), 1.91 (1H, m), 1.29 (3H, t).
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:17])([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)[CH3:8])(=O)=O.[I-:18].[Na+].O>CN(C)C=O>[I:18][CH2:6][C:7]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:17])[CH3:8]
Reactant: [I-]
Reactant: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CI)n1cc([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of the crude 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propyl methanesulfonate (18 g) obtained in Step A of Example 115 in N,N-dimethylformamide (150 mL) was added sodium iodide (20 g), and the mixture was stirred overnight at 130° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14 g).
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12](O)[CH2:13][CH2:14]/[CH:15]=C\CCCCCCC)[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:26]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30]C(C)C)=[O:27]>>[CH2:1]([C@@H:7]1[C:8](=[O:25])[O:9][C@@H:10]1[C@@H:11]([O:36][C:34](=[O:35])[C@H:29]([CH3:30])[NH:28][CH:26]=[O:27])[CH2:12][CH2:13][CH:14]=[CH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC/C=C\CC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Product: C=CCC[C@H](OC(=O)[C@H](C)NC=O)[C@H]1OC(=O)[C@H]1CCCCCC

Procedure:
by esterifying (S)-3-hexyl-(S)-4-[(R,Z)-2-hydroxy-5-tridecenyl)-2-oxetanone with N-formyl-L-leucine there was obtained
Reaction SMILES: C(OC(Cl)=O)C.[C:7]([NH:17][CH2:18][C:19]([OH:21])=O)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CN1CCOCC1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]([N:39]([CH3:41])[CH3:40])[CH3:38])=[CH:32][CH:31]=1>O1CCCC1>[C:7]([NH:17][CH2:18][C:19]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]=[C:37]([N:39]([CH3:40])[CH3:41])[CH3:38])=[CH:34][CH:35]=1)=[O:21])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(=Nc1ccc(N)cc1)N(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=Nc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1)N(C)C
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
22.8 g (0.21 mol) of chloroformic acid ethyl ester were added dropwise at -15° C to a solution of 41.8 g (0.2 mol) of N-(carbobenzoxy)-glycine and 21.3 g (0.21 mol) of N-methylmorpholine in 250 ml of absolute tetrahydrofuran. The mixture was stirred for 10 minutes at -10° C and was then filtered. A solution of 33.7 g (0.19 mol) of N'-(4-aminophenyl)-N,N-dimethylacetamidine in 100 ml of absolute tetrahydrofuran was added dropwise to the filtrate at -10° C. The mixture was then stirred for 30 minutes at -10° C, 1 hour at 0° C and 2 hours at room temperature. Thereafter, the mixture was concentrated on a rotary evaporator, suspended in sodium hydroxide solution and repeatedly extracted with chloroform. The chloroform phase was dried with Na2SO4 and concentrated. The residue was recrystallized from benzene-ligroin. 39.2 g of N'-[4-(carbobenzoxyglycylamino)-phenyl]-N,N-dimethylacetamidine of melting point 133° C were thus obtained and were slowly introduced into 800 ml of HBr/glacial acetic acid, with cooling. The mixture was stirred for 2 hours at room temperature and was then stirred into 2 liters of dry ether. A crystalline precipitate formed and this was filtered off, washed with ether and then dissolved in water. The aqueous solution was rendered alkaline, with cooling, and was repeatedly extracted with chloroform. The organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from toluene to afford 22.9 g (51% of theory) of N,N-dimethyl-N'-(4-glycylaminophenyl)acetamidine, melting point 142°-145° C.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C[Si](C)(C)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[O:15])=[CH:10][CH:9]=1>C1COCC1.C1(C)C=CC=CC=1>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=2)([OH:15])[CH:1]=[CH2:2])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)Oc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: C=C[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Eb) 30.2 ml of 15% vinylmagnesium chloride solution in THF are added dropwise at 0° C. to a solution of 5.58 g of 4-trimethylsilyloxyphenyl-(4-bromo-phenyl)-methanone in 80 ml of toluene. The mixture is stirred at 0° C. for 2 h., then at room temperature for 2 h., subsequently hydrolyzed with 40 ml of ammonium chloride solution and extracted with methylene chloride. The extracts are dried, evaporated and purified over silica gel with toluene-acetone as the eluent. There are obtained 2.8 g of (RS)-4-[1-(4-bromophenyl)-1-hydroxy-allyl]-phenol, MS: m/e 304 (M+H+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl.C(N(C(C)C)C(C)C)C>[C:36]1([S:42]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]3[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=3)([CH3:12])[CH3:11])=[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH:3]=2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(NS(=O)(=O)c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a solution of 100 mg (0.2 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 4 ml dichloromethane and 85 μl N-ethyldiisopropylamine were added 56 μl (0.436 mmol) benzenesulfonyl chloride and the mixture was stirred over night at room temperature. The reaction mixture was washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Chromatography of the residue afforded 26 mg (28%) of the title compound as a white foam.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9]([O:11]C)=[O:10])[CH:6]=1.[OH-].[Li+]>C1COCC1.O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:13][C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[CH:6]=1
Reactant: COC(=O)CC(Cn1cc(I)cn1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(Cn1cc(I)cn1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of dimethyl 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinate (200 mg, 0.61 mmol) and lithium hydroxide (40 mg, 1.80 mmol) in THF/water (4 mL/1 mL) was stirred at 60° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinic acid. MS ESI calc'd. for C8H10IN2O4 [M+H]+ 325. found 325. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.50 (s, 1H), 4.60-4.48 (m, 2H), 3.46-3.38 (m, 1H), 2.83-2.73 (m, 1H), 2.60-2.51 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O)(=O)C.BrBr>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Yield: 93.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-4,5-dihydropyridazinone (11.75 g) and glacial acetic acid (100 ml) was added dropwise 3 ml of bromine and the mixture was heated at 60°-70° C. for 3 h. The resulting mixture was cooled and slowly poured into 400 ml of cold water. The resulting white solid was filtered and dried to yield 10.83 g (89%) of 6-(4-chlorophenyl)pyridazinone.