Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)[N:10]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:28]2[CH2:33][CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[C@H:30]([CH3:34])[CH2:29]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN[C@H](C)C1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN(CC(N)=O)[C@H](C)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine (32 mg, 0.07 mmol), 2-bromoacetamide (29 mg, 0.21 mmol), sodium carbonate (44 mg) and DMA (1 mL) is heated at 60° C. under nitrogen with magnetic stirring for 18 h. The reaction mixture is allowed to cool and partitioned between EtOAc (8 mL) and water (2 mL). The organic layer is separated, washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% Ammonium hydroxide) provides the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.06-7.26 (m, 5H), 6.81-6.83 (m, 2H), 5.58 (br d, J=6.3 Hz, 1H), 4.97 (dd, 2H), 3.77-3.86 (m, 2H), 3.25-3.33 (m, 2H), 2.80-3.00 (m, 4H), 2.45-2.62 (m, 5H), 2.22 (s, 3H), 2.16 (s, 6H), 1.27 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH2:14][C:15]([Cl:21])=[O:17]
Reactant: COc1cc(Br)c(CC(=O)O)cc1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(Br)c(CC(=O)Cl)cc1OC(F)F
Temperature: 25 °C

Procedure:
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid (350 mg, 1.12 mmol) was dissolved in 6 ml dichloromethane and 0.1 ml oxalyl chloride and 0.01 ml DMF was added. The solution was stirred at room temperature until gas evolution stopped, then concentrated under reduced pressure. Dichloromethane (6 ml) was added to the residue and the solvent removed again to assure that all the oxalyl chloride was removed giving 118 mg of crude (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride.
Reaction SMILES: [CH:1]([CH:4]([C@H:14]1[CH2:17][C@H:16](CS([O-])(=O)=O)[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]([CH:4]([C@@H:14]1[CH2:15][C@H:16]([N:27]2[CH:28]=[N:29][C:30]3[C:26]2=[N:25][CH:24]=[N:23][C:31]=3[NH2:32])[CH2:17]1)[C:5]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[O:6][SiH3:7])([CH3:3])[CH3:2]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CC(C)C([C@H]1C[C@H](CS(=O)(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C([C@H]1C[C@@H](n2cnc3c(N)ncnc32)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 120 °C

Procedure:
In a 25 mL three-neck flask with trans-3-(triisopropyl-siloxyethyl)cyclobutyl -mesylate (0.27 g, 7.7 mmol), adenine (0.16 g, 1.18 mmol) and Cs2CO3 (0.38 g, 1.17 mmol) inside, dry DMF 5 mL was added under argon. Then began to heat to 120° C. and after 24 hr, the solvent was removed and directly applied to silica gel flash chromatography to give 0.14 g (47%) the desired product. 1H NMR (CDCl3, 400 MHz): δ 0.99-1.05 (m, 21H), 1.72-1.78 (m, 2H), 2.15-2.23 (m, 2H), 2.60-2.79 (m, 3H), 3.67-3.70 (t, J=6.0, 2H), 4.81-4.90 (m, 1H), 6.37-6.39 (bs, 2H), 7.88 (s, 1H), 8.31 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 12.08, 18.17, 26.60, 37.03, 39.84, 45.86, 61.64, 138.76, 140.09, 150.07, 152.91, 155.93. MS (FAB): expected for C20H35N5OSi (M+H)+ 390.61. Found 390.26828. IR (neat) νmax 2942, 2865, 1670, 1604, 1571, 1463, 1415, 1308, 1246, 1108, 882, 681, 658.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].[Cl-].[Li+]>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 40 °C

Procedure:
A suspension of 2.54 g of 5-chloro-3-iodopyridin-2-ylamine, 2.12 ml of ethynyltrimethylsilane, 0.38 g of copper iodide and 0.47 g of lithium chloride in 7 ml of triethylamine and 75 ml of dimethylformamide is degassed under argon for approximately 15 minutes. 0.408 g of [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) chloride is added to the above suspension. The mixture is heated at around 40° C. for approximately 19 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.63 g of 5-chloro-3-trimethylsilanylethynylpyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6]N.[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)[CH:13]=[CH:14][N:15](C)C)[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[N:6]([CH2:5][CH2:4][O:3][CH3:2])[N:15]=[CH:14][CH:13]=1)=[O:19])[CH3:9]
Reactant: COCCNN
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccnn1CCOC
Temperature: 60 °C

Procedure:
2-Methoxyethylhydrazine hydrochloride (Ref: J. Med. Chem. (1967) 11 (1) 79-83) (1.07 g, 8.5 mmol) and ethyl-4-dimethylamino-2-oxo-but-3-enoate (1.5 g, 8.5 mmol) were dissolved in ethanol (10 ml) and heated at 60° C. for 7 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (80 ml) and dilute sodium carbonate solution (40 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent removed in vacuo to give a brown gum. This material was chromatographed on silica gel (30 g) using 40% to 20% heptane in ethyl acetate. The higher running product was collected to give 2-(2-methoxyethyl)-2H-pyrazole-3-carboxylic acid ethyl ester as 750 mg of a mobile yellow oil. The lower running product was collected to give 1-(2-methoxyethyl)-1H-pyrazole-3-carboxylic acid ethyl ester as 360 mg of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](O)[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([Cl:18])[C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1ccc(SC)cc1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)C(Cl)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the hydroxy-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester of Step 2 (1.0 eq) in CH2Cl2 (0.2M) was added SOCl2 (5 eq). The resulting mixture was stirred at room temperature for 12 h, poured in saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9.5:0.5) afforded the desired compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[O:49][N:48]=1>CN(C=O)C.C1COCC1>[O:49]1[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:47]([CH2:46][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:48]1
Reactant: BrCc1noc2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3noc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a stirring solution of 390 mg (0.86 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL of DMF at 0° C. is added 1.03 mL (1.03 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 200 mg (0.94 mmol, 1.1 equiv.) of 3-bromomethyl benzo[d]isoxazole (Uno, H.; Kurokawa, M.; Natsuka, K.; Yamato, Y.; Nishimura, H. Chem. Pharm. Bull. 1976, 24, 632)in 1 mL of DMF is added. The resulting solution is stirred for 14 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 303 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.81 (d, 1H, J=7.8), 7.55-7.10 (m, 14H), 6.97 (m, 2H), 5.01 (m, 1H), 4.28 (m, 3H), 3.85 (m, 4H), 3.58 (dd, 1H, J=5.1, 16.6), 1.07 (d, 6H, J=6.6); low resolution MS (FAB)m/e 589 (MH+), 588 (M+), 424, 396; Anal. (C35H32N4O5) Calcd. C, 71.41; H, 5.48; N, 9.52 Found C, 71.48; H, 5.49; N, 9.47.
Reaction SMILES: B(O)(O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH:6]1[C:7]2[C:3](=[C:2]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccc2[nH]ccc12
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: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc3[nH]ccc23)c2c(N)ncnc21
Temperature: 80 °C
Yield: 50 %

Procedure:
A solution of 1H-indol-4-yl-4-boronic acid (40 mg, 0.25 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.1 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA91 (14.6 mg, 50% yield). ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][C:23]=1[F:32]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][C:23]=1[F:32])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2F)c1

Procedure:
Prepared from 2-(3-Acetyl-phenoxy)-nicotinic acid and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol. mp 68-70° C.
Reaction SMILES: [Mg].[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([Mg]Cl)[C:5]=2[O:4]1.C[CH:18](OC(C)=O)[O:19]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[C:5]=2[O:4]1
Reactant: FC1(F)Oc2c([Mg]Cl)cccc2C1(F)F
Reactant: CC(=O)OC(C)OC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: CCCCCCCC
Solvent: Cc1ccccc1
Product: OCc1cccc2c1OC(F)(F)C2(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above is decanted into a clean, dry reaction vessel, leaving the unreacted magnesium turnings in the first vessel. This solution containing 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmagnesium chloride is heated at reflux, and 16.5 grams (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, commercially available from E.I du Pont De Nemours & Co., Inc. Wilmington Del., under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, is added with stirring during about a three hour period. Upon completion of addition, the reaction mixture is heated at reflux for an additional four hours and then is allowed to cool to ambient temperature as it stood for about 18 hours. The reaction mixture is warmed to about 53° C. and then is poured into 100 grams of ice, 52 grams of concentrated hydrochloric acid, and 200 grams of a mixture of 95% n-octane and 5% toluene (wt/wt). This mixture is filtered, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[CH3:2].C(Cl)(Cl)Cl.Cl[CH2:27][N:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29](=[O:33])[O:30][CH2:31][CH3:32]>C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:21])[N:14]([CH3:20])[N:15]=[C:16]([CH3:19])[C:17]=1[O:18][CH2:27][N:28]([C:29]([O:30][CH2:31][CH3:32])=[O:33])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCOC(=O)N(CCl)c1ccccc1
Reactant: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(COc1c(C)nn(C)c(=O)c1-c1c(CC)cc(C)cc1CC)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a mixture of 0.30 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-3(2H)-pyridazinone [compound (II-1-2)] and 5 mL of chloroform, 0.22 mL of triethylamine and 0.52 mL of ethyl N-chloromethyl-N-phenylcarbamate were added, followed by stirring at room temperature for 13.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.27 g of 4-(2,6-diethyl-4-methylphenyl)-5-(N-ethoxycarbonyl-N-phenylaminomethoxy)-2,6-dimethyl-3(2H)-pyridazinone [compound (I-6-1)].
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:27])[C:23](O)=[O:24]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)ccc1F
Product: CC(C(=O)NCc1cc(F)ccc1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=491.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(2,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCC2CN(Cc3ccccc3)CC12
Solvent: ClCCl
Product: O=C1CCC2CN(C(=O)OCc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
Benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added dropwise to a solution of 7-benzyl-2-oxo-7-azabicyclo[3.3.0]octane (5.20 g, 24.2 mmol) in dichloromethane (50 ml) under cooling with ice, followed by stirring at room temperature for 24 hours. The mixture was again cooled with ice, and benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added thereto dropwise. After removing the solvent by evaporation, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4.52 g (17.4 mmol, 72%) of the title compound as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[OH:25][CH:26]([CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]1)[CH2:27][NH2:28]>C(O)C>[OH:25][CH:26]([CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]1)[CH2:27][NH:28][C:4](=[O:3])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]([F:13])([F:14])[F:15])[C:6]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: CCOC(=O)c1cc(F)cc(C(F)(F)F)c1OCc1ccccc1
Solvent: CCO
Product: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2OCc2ccccc2)O1
Temperature: 100 °C

Procedure:
3.42 g (10 mmol) of 2-benzyloxy-5-fluoro-3-(trifluoromethyl)-benzoic acid ethyl ester is dissolved in 10 ml of ethanol, 2.43 g (15 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine is added, the ethanol is distilled off and the remaining oil is warmed to 100° C. in a vacuum in 2 hours. The reaction mixture is then dissolved in 50 ml of ethyl acetate, shaken out twice with 10 ml of 1N hydrochloric acid each, the organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 2.18 g (7.18 mol) =47.68% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(#N)C>[CH2:9]([N:11]([CH2:12][CH3:13])[C:3]([NH:4][N+:5]([O-:7])=[O:6])=[NH:8])[CH3:10]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)C(=N)N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
To a mixture of 1.35 g of S-methyl-N-nitroisothiourea and 5 ml of acetonitrile was added 0.88 g of diethylamine, followed by stirring for 6 hours in an oil bath of 60° C. The reaction mixture was concentrated and the residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to afford 0.85 g of N,N-diethyl-N'-nitroguanidine as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1.CCN(CC)CC>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)C2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2 mmol) in THF (100 mL) was added a solution of ZnCl2 (1M in ether; 16.2 mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added in small portions, followed by the dropwise addition of Et3N (1.63 g; 16.2 mmol) in 10 mL of THF. The reaction was then stirred at RT overnight. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 2.2 g (50% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (s, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H), 8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min. LRMS (M+) 329.1, 331.0.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:40][N:20]([CH:21]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH:18]([C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2N(C)C(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 48.6 %

Procedure:
A solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.24 g), iodomethane (77 mg) and K2CO3 (82 mg) in DMF (5 ml) was stirred for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[N-methyl-N-[1-(4,5-diphenyloxazol-2-yl)ethyl]amino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.12 g). MS (m/z): 511 (M+ +1) IR (Film): 1730 cm-1NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.63 (3H, d, J=7.1 Hz), 1.58-1.88 (3H, m), 1.95-2.18 (1H, m), 2.26 (3H, m), 2.46-2.68 (1H, m), 2.80-3.00 (1H, m), 4.12 (2H, q, J=7.1 Hz), 4.26 (3H, q, J=7.1 Hz), 4.60 (2H, s), 6.56 (1H, d, J=7.9 Hz), 7.11 (1H, dd, J=7.9, 7.9 Hz), 7.26-7.50 (7H, m), 7.59-7.68 (4H, m)