Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1CO[Si](C)(C)C
Temperature: 70 °C
Yield: 65.1 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc—hexanes) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:15])=[O:10]
Reactant: Cc1cc(/C=C/C(=O)O)c(C)s1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(/C=C/C(=O)Cl)c(C)s1

Procedure:
To a solution of (E)-3-(2,5-dimethylthiophene-3-yl)acrylic acid (328 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-3-(2,5-dimethylthiophene-3-yl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 367.91; mp:>230° C.; 1H-NMR (CDCl3) δ: 8.98-8.83 (2H, m), 8.25-8.16 (1H, m), 8.10-8.02 (1H, m), 7.76-7.68 (2H, m), 7.60-7.42 (3H, m), 6.78-6.73 (1H, m), 6.61 (1H, d, J=16.1 Hz), 2.75 (3H, s), 2.38 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reactant: ClCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(OCc3ccccc3)nc2-c2ccc(F)cc2)cc1

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 6) (200 mg, 0.54 mMol), silver carbonate (150 mg, 0.54 mMol) and benzyl chloride (1 ml) were stirred in acetone (100 ml) and dimethylformamide (25 ml) at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to a white solid which was recrystallized from chloroform-methanol: m.p. (DSC): 204.81° C. Anal. Calc'd. for C26H19N2O3SF (458.52): C, 68.11; H, 4.18; N, 6.11. Found: C, 67.81; H, 4.16; N, 6.04.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=[O:28])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(C)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (6.20 mL)-acetonitrile (6.20 mL)-water (6.20 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copperbenzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphtyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C[Mg]Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Under an argon atmosphere, a solution of 10.40 g of N-methoxy-N-methyl-p-toluamide in 100 ml of tetrahydrofuran was ice-cooled and 4-methylbenzylmagnesium chloride (solution prepared by dissolving 10.60 g of α-chloro-p-xylene and 1.94 g of magnesium in 85 ml of tetrahydrofuran) was added dropwise. After stirring for one hour, 100 ml of 10% hydrochloric acid was slowly added. The reaction solution was diluted with water, extracted with diethyl ether, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the crude crystal was washed with diisopropyl ether and then dried under reduced pressure to obtain 8.43 g of the desired compound as a colorless crystal having a melting point of 93 to 100° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(=O)([O-])[O-].[F:23][C:24]([F:29])([F:28])[C@@H:25]1[CH2:27][O:26]1>C1COCC1>[F:23][C:24]([F:29])([F:28])[C@@H:25]([OH:26])[CH2:27][N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (2.01 g, 7.88 mmol, 1.0 eq), was placed in THF (100 mL) and MP-carbonate (7.1 g) was added. The reaction was stirred in a sealable vessel for 1 hour and then (S)-2-trifluoromethyl-oxirane (1.30 g, 11.59 mmol, 1.00 mL, 1.47 eq) was added. The reaction vessel was sealed, stirred at room temperature for 1 hour, and then heated at 50° C. overnight. The reaction was then cooled to room temperature and filtered. The resin was washed with CH2Cl2 (150 mL) and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain (S)-1,1,1-trifluoro-3-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange solid (2.27 g, 95%). m.p.=82-85° C.; LCMS (m/e) 305 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06-7.99 (m, 2H), 7.31-7.26 (m, 1H), 4.16-4.02 (m, 2H), 3.15-2.97 (m, 4H), 2.96-2.81 (m, 3H), 2.81-2.67 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:18]O>>[CH3:18][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])c[nH]c1C(=O)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of sodium nitrite (714 g, 10.2 mol) in 700 ml of water at 50° C.±5° C. was added over a period of 3 hours a solution of mucobromic acid (48) (700 g, 2.7 mol) in 700 ml of warm ethanol. The reaction was stirred for 15 minutes, cooled to 0° C., and 700 ml of ethanol was added. The resulting orange precipitate was collected by vacuum filtration and dried in vacuo to yield sodium nitromalondialdehyde monohydrate (305 g, 1.9 mol) which was used in the next step without further purification. Glycine ethyl ester (300 g, 2.9 mol) and nitromalondialdehyde monohydrate (305 g, 1.9 mol) were placed in a 12 l round bottom flask and slurried with a mechanical stirrer in 560 ml of methanol and 280 ml of water. Sodium hydroxide (800 g, 20 mol) dissolved in 1.6 l water was added to the solution at a rate which maintained the temperature at 50° C. The reaction was cooled to 0° C. with an ice bath and neutralized to pH 0 with 1.7 1 HCl (conc.) while maintaining the temperature below 10° C. A black precipitate was removed by filtration through Celite and the product was extracted with 20 liters of ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) as a brown solid which was used without further purification. To a solution of 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) dissolved in 180 ml of methanol was added 8 ml of concentrated sulfuric acid. The solution was refluxed for 15 hours, cooled to 0° C. and 90 ml of water was added. The solution was then allowed to stand at -20° C. for 2 days. The resulting light brown crystals were collected by vacuum filtration to yield pure methyl 4-nitropyrrole-2-carboxylate (49) (105 g, 0.62 mol) in 23% overall yield. 1H NMR (DMSO-d6) δ 14.2 (br s, 1H), 7.74 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=1.7 Hz), 3.73 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12].O>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(F)c1C#N

Procedure:
2,6-Difluorobenzonitrile, 2.78 g (20 mmol) and 5 ml (60 mmol) of 40% aqueous methylamine in 50 ml DMF is stirred at room temperature for 1 hr., poured into water and the product is collected, 2.4 g m.p. 130°-132° C.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:17](OCC)(=O)C>O1CCCC1>[CH3:17][CH:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(C)=O
Reactant: COC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
9.91 Gram (95%, 56.9 mmol) of tert-butyl methyl malonate was dissolved in 120 mL of tetrahydrofuran (THF), and the resulting solution was added dropwise to a suspension containing 2.28 g (60 wt %, 56.9 mmol) of sodium hydride (NaH) and 120 mL of THF at 0° C. over 0.5 hours, followed by stirring for 0.5 hours. Thereafter, a solution containing 8.08 g (56.9 mmol) of methyl iodide (MeI) and 20 mL of TI-IF was added dropwise over 0.5 hours, and the resulting mixture was stirred at 0° C. for 0.5 hours and further stirred at 25° C. for 5 hours. After adding 200 of ethyl acetate, the organic layer was washed, in order, twice with saturated brine and twice with water, and dried over sodium sulfate, and the solvent was concentrated to obtain 13.0 g of 1-tert-butyl 3-methyl 2-methylmalonate as a colorless transparent oil. Subsequently, 45.9 g of an aqueous formalin solution was added to 13.0 g of the oil, and resulting mixture was cooled to 0° C. Furthermore, 7.81 g of potassium carbonate was added, and the mixture was stirred at 0° C. for 1 hour and further stirred at 25° C. for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated sodium hydrogensulfite solution and twice with water, and dried over sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 mL of pyridine. The resulting solution was cooled to 0° C., and 21.7 g of p-toluenesulfonyl chloride was added thereto. The obtained mixture was stirred at 0° C. for 2 hours and then stirred at 60° C. for 4 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in order, three times with an aqueous saturated ammonium chloride solution and twice with water, and dried over sodium sulfate. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4/1) to obtain 15.8 g of the objective Compound (I-31) as a colorless transparent oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.C(#N)C.O>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1Br
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combined with 10 g of H2O. 1.11 g (10.45 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 14 mg of CuBr and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL acetonitrile under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 2 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The purity was determined by 1H NMR to be >99%.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:9]2[N:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:11]=1
Reactant: O=c1[nH]nc(-c2ccccc2)c2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nnc(-c2ccccc2)c2cccnc12
Temperature: 110 °C
Yield: 80.1 %

Procedure:
To 5-phenylpyrido[2,3-d]pyridazin-8(7H)-one (1.39 g, 6.2 mmol) and pyridine (0.50 ml, 6.2 mmol) was added phosphorus oxychloride (12 ml, 125 mmol). The slurry was heated to 110° C. for 1 hour. After cooling to room temperature, the reaction was poured into 200 mL of ice-water. The mixture was extracted with 4×50 mL of chloroform. The chloroform layer was washed with 1×50 mL H2O, 1×50 mL 1N NaOH, and 1×50 mL of H2O. The organic layer was dried over Na2SO4, filtered, and concentrated. Silica gel column chromatography afforded 8-chloro-5-phenylpyrido[3,2-d]pyridazine 71 (1.2 g). 1H-NMR (400 MHz, CDCl3): δ 9.42 (d, J=2.7 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 7.89 (m, 1H), 7.73 (br s, 2H), 7.61 (br s, 3H). MS 241.0 (calc'd) 242.0 (M+H, found).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:22])[O:11][C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C1COCC1>[CH2:52]([O:51][C:49](=[O:50])[O:14][C:13]1[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[O:11][C:10](=[O:22])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:53]
Reactant: CCOC(=O)Cl
Reactant: CON1CCC2(CC1)OC(=O)C(c1cc(C)ccc1C)=C2O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2cc(C)ccc2C)C(=O)OC12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (120 mg, 0.40 mmol), triethylamine (0.08 ml, 60 mg, 0.60 mmol) and 4-dimethylaminopyridine DMAP (2 mg, 0.02 mmol) in 4 ml THF at 0° C. was added a solution of ethyl chloroformate (0.05 ml, 52 mg, 0.50 mmol) dissolved in 1 ml THF dropwise. The suspension was kept at 0° C. for 30 minutes under argon and left stirring at room temperature overnight. Then the solvent was removed under vacuum. Ethyl acetate was added to the residue and the precipitation was filtered off. The filtrate was concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:9). Yield: 111 mg of carbonic acid 3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-oxa-8-aza-spiro[4.5]dec-3-en-4-yl ester ethyl ester (title compound P1.1) as a light yellow gum.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CC=C(c3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0051 mol) of 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in 40 ml of dimethylformamide was treated with 2.13 ml (0.0153 mol) of triethylamine and 0.62 g (0.00170 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica with methanol as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. The organic phase was then completely freed from the solvents and the residue was digested in diethyl ether and subsequently filtered off under suction. A total of 0.27 g (56%) of 5-(4-phenyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1>>[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][C:3](=[O:5])[C:2]([CH3:1])=[CH:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: CC(=Cc1ccccc1)C(=O)O
Product: CC(=Cc1ccccc1)C(=O)Nc1ccc2nc(N3CCC(N(C)C)C3)sc2c1
Yield: 12.5 %

Procedure:
Prepare according to Method B, using α-methylcinnamic acid (99 mg, 0.610 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to yield the title compound (31 mg, 12%). mass spectrum (m/e): 407.3 [M+H], 405.2 [M−H].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CC=CC=1.[C:64](OC(=O)C)(=[O:66])[CH3:65]>ClCCl>[C:64]([O:50][CH:45]1[CH2:44][CH2:43][CH:42]([CH:41]=[C:40]([CH:24]2[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28](=[O:29])[CH:30]([CH2:35][CH:36]=[CH2:37])[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]3[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]3[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]3[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:21](=[O:22])[O:23]2)[CH3:51])[CH2:47][CH:46]1[O:48][CH3:49])(=[O:66])[CH3:65]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CC(=O)OC(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 5 h

Procedure:
To a solution of the FR-900506 substance (10.4 mg) in dichloromethane (0.2 ml) were added pyridine (0.1 ml) and acetic anhydride (0.35 ml) at room temperature, and the mixture was stirred for 5 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: diethyl ether and dichloromethane, 1:2 v/v) to give 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.0 mg).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41](S([O-])(=O)=O)C>>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH2:8][CH3:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(=O)(=O)[O-]
Reactant: C[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1

Procedure:
(R)-7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;