Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:10][OH:11].C1(C(C)C)C=CC=CC=1.C1(O)C=CC=CC=1.CC(C1C=CC=CC=1)=C>CC(C)=O>[C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]=[O:11]
Reactant: [O-]O
Agent: C=C(C)c1ccccc1
Solvent: Oc1ccccc1
Solvent: CC(C)c1ccccc1
Solvent: CC(C)=O
Product: O=O

Procedure:
It has been discovered that when a cumene oxidation product mixture containing cumene hydroperoxide (CHP) and DMPC is decomposed to produce phenol, acetone and alpha-methyl styrene by passing the cumene oxidation product mixture into a decomposing vessel containing indirect heat exchange surfaces wherein the cumene oxidation product mixture and an incoming circulating stream comprising cumene hydroperoxide, phenol, acetone and an acid catalyst are admixed, reacted and cooled by passage around the indirect heat exchange surfaces and then circulating a cooled stream comprising unreacted cumene hydroperoxide, phenol and acetone from the decomposing vessel to provide the circulating stream referred to hereinabove, an improved yield of alpha-methyl styrene is realized. A net reacted stream preferably comprising a cumene hydroperoxide concentration from about 0.5 to about 5 weight percent is removed from the circulating stream and recovered. The cumene oxidation product mixture is the result of cumene oxidation with oxygen and preferably comprises a cumene hydroperoxide concentration from about 60 to about 95 weight percent. The ratio of the flow rate of the cumene oxidation product mixture to the flow rate of the circulating stream is preferably from about 1:10 to about 1:100 in the decomposing vessel. In accordance with the present invention, a suitable and preferred acid catalyst is sulfuric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>COC(C)(C)C.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:18][C:9]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1ccccc1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of aniline (1.32 g, 14.19 mmol) in tert-butyl methyl ether (25 ml) and water (25 ml) was added sequentially 2-iodoheptafluoropropane (5.00 g, 17.06 mmol), sodium thiosulphate (3.50 g, 17.06 mmol), sodium hydrogen carbonate (1.73 g, 17.06 mmol) and tetrabutylammonium hydrogen sulphate (0.53 g, 17.06 mmol). The reaction mixture was stirred at room temperature for 18 h and the two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with hydrochloric acid (2N), aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and concentrated in vacuo to give the titled compound (1.00 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OC[C@H]1CCNC1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 186.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2) and (S)-1-pyrrolidin-3-yl-methanol. HPLC (Condition 4) tR=6.17 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=476.2/478.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14]>CO.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:1])[CH3:18])=[O:17])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1ccc(N)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
To a solution of N,N-dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10 g, 25.2 mmol) in MeOH (100 mL) stirred under N2 at 20° C. was added Pd/C (1 g, 9.40 mmol) in one charge. The reaction mixture stirred under a H2 atmosphere at 20° C. for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the desired product 4-amino-N,N-dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol, 94.0% yield). TLC (DCM/MeOH=10:1, Rf=0.4): 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J=8.2 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8.2 Hz, 1H), 3.95 (br. s., 2H), 3.08 (s, 3H), 2.80 (s, 3H); ES-LCMS m/z 233.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH3:13])[C:10]([CH:16]3[CH2:18][CH2:17]3)([C:14]#[N:15])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH:16]3[CH2:17][CH2:18]3)([C:14]#[N:15])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: CC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 49.4 %

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (2.6 g) obtained in Step C of Example 357 was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (820 mg) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (1.3 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (810 mg) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=900/100) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=900/100) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a longer retention time.
Reaction SMILES: C(N1C=CN=C1)C1C=CC=CC=1.OCC1NC=CN=1.N1C=CN=C1C=O.C(SC)(=S)NN.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=[N:39][NH:40][C:41]([S:43]C)=S>C(O)(=O)C.C(O)C>[N:33]1[CH:37]=[CH:36][N:35]2[C:34]=1[CH:38]=[N:39][NH:40][C:41]2=[S:43]
Reactant: CSC(=S)NN=Cc1ncc[nH]1
Agent: CSC(=S)NN
Agent: O=Cc1ncc[nH]1
Agent: OCc1ncc[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: S=c1[nH]ncc2nccn12
Temperature: 25 °C

Procedure:
N-Benzylimidazole is converted to 2-hydroxymethylimidazole by the method of R. G. Jones, J.A.C.S. 71, 383 (1949). The 2-hydroxymethylimidazole is converted to imidazole-2-carboxaldehyde by the method of H. Schubert and H. D. Rudorf, Angew. Chem. Intern. Ed., 5, 674 (1966). A 67.) gm. portion of imidazole-2-carboxaldehyde is added to 500 ml. of ethanol and warmed on a steam bath. An 85.4 gm. portion of methyl dithiocarbazate is added together with 200 ml. of ethanol. While the solution is warm, 20 drops of glacial acetic acid are added. The mixture is heated to reflux on a steam bath for one hour, cooled and filtered. The filtrate is evaporated yielding 123.2 gm. of 3-(2-imidazolymethylene)-dithio-carbazic acid, methyl ester. A 120.2 g. portion of 3-(2-imidazolylmethylene)dithio-carbazic acid, methyl ester is added to 800 ml. of diphenyl ester. The mixture is heated in an oil bath at 195°-200° C. for 15 minutes. The reaction mixture is cooled to room temperature and the precipitate is collected, washed with petroleum ether, and air dried. This light orange solid is crystallized twice from petroleum ether giving 83.0 gm. of imidazo[1,2-d]-as-triazine-5(6H)-thione, m.p. 238°-240° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)([CH2:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[N+:13]([O-:15])=[O:14])=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH2:27][CH2:28][CH2:29][NH2:30])([CH2:16][CH2:17][CH2:18][NH2:19])[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCC(CCCNC(=O)OC(C)(C)C)(CCCNC(=O)OC(C)(C)C)[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC(CCCN)(CCCN)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of tris(3-(tert-butoxycarbonylamino)propyl)nitromethane 1c (10 g, 18.8 mmol) in trifluoroacetic acid (20 ml) and dichloromethane (50 ml) was stirred at room temperature for 4 h. The reaction was then concentrated under high vacuum to afford the title compound 10c (10.8 g, 18.8 mmol. 100%) as a gum.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=O)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Reactant: COc1ccc(CCOS(C)(=O)=O)cc1
Product: COc1ccc(CCN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 21.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-2-(4-methoxyphenyl)ethane (0.38 g) as starting materials, N-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=O)=[CH:3]1.[S:23]([NH:33][NH2:34])([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CO>[S:23]([NH:33][N:34]=[C:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH2:20][OH:21])[C:4](=[CH:3][CH:2]([OH:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)([C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=1)(=[O:24])=[O:25]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CCC5=CC(O)CC[C@]5(CO)[C@H]4CC[C@]23C)cc1
Reaction time: 16 h

Procedure:
3,19-Dihydroxyandrost-4-en-17-one (19) is heated under reflux in methanol with one equivalent of p-toluenesulfonylhydrazide (TsNHNH2, a) for 16 hours. After cooling, the mixture is evaporated to give the crude product. Purification yields the tosylhydrazone (20).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[F:20][C:21]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:22]=1[O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[O:19]=[C:11]1[N:10]([CH:9]([N:27]2[CH2:26][CH2:25][CH:24]([O:23][C:22]3[C:30]([F:37])=[C:31]([F:36])[C:32]([F:35])=[C:33]([F:34])[C:21]=3[F:20])[CH2:29][CH2:28]2)[CH2:8][CH3:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12]1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1)n1c(=O)[nH]c2ccccc21
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
A mixture of 10 g of sodium bicarbonate, 3.58 g of 1-(3-chloropropyl)-1,3-dihydro-2-oxo-2H-benzimidazole and 60 ml of dimethylformamide was treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 20 ml dimethylformamide and stirred at 75° C. for 1.5 hours. The reaction mixture was then cooled and filtered. The filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). Recrystallization from isopropyl ether afforded 3.6 g (54%) of 1-[1-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 117°-120° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:18]1[N:23]=[C:22](C=O)[CH:21]=[CH:20][CH:19]=1.[CH:26]([C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:30]=1[NH2:31])([CH3:28])[CH3:27]>C(O)=O.CO>[OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:4][C:3]=1[C:18]1[NH:23][C:22](=[N:31][C:30]2[C:32]([CH:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=[CH:35][C:29]=2[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)(C)c1cc(-c2ccccc2)c(O)c(-c2cccc(C=O)n2)c1
Solvent: O=CO
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(-c2cc(C(C)(C)C)cc(-c3ccccc3)c2O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 6-(2′-hydroxy-3′-phenyl-5′-tert-butylphenyl)-2-formyl-pyridine (12) (3.17 g, 9.17 mmol) in the minimum volume of methanol was added 2,6-diisopropylaniline (1.79 g, 10.1 mmol). After the addition of a few drops of formic acid, the solution was stirred overnight. The cloudy yellow reaction mixture was then filtered through a frit, and the solid washed with methanol (3×5 mL), giving compound 13 as a yellow solid. Yield: 2.92 g (65%).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].[F:62][C:63]([F:71])([F:70])[CH:64]1[CH2:69][NH:68][CH2:67][CH2:66][NH:65]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[N+:11]([C:4]1[CH:3]=[C:2]([N:68]2[CH2:67][CH2:66][NH:65][CH:64]([C:63]([F:71])([F:70])[F:62])[CH2:69]2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: FC(F)(F)C1CNCCN1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(N2CCNC(C(F)(F)F)C2)c2occc2c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 444.1 %

Procedure:
To 7-iodo-5-nitro-1-benzofuran (231.4 mg, 0.08 mmol) the following was added: Xantphos (92.6 mg, 0.16 mmol), Pd2 dba3 (36.6 mg, 0.04 mmol), sodium tert-butoxide (215.4 mg, 2.24 mmol), 2-(trifluoromethyl)piperazine (148.1 mg, 0.96 mmol; Intermediate 45) and xylene (23 mL). The resulting mixture was stirred at 100° C. for 3 days. Filtration through Celite and purification by flash chromatography, using EtOAc:heptane (1:1) as eluent, furnished 1-(5-nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine (112 mg, 44% yield). HPLC 90%, RT=1.648 min (System A; 10-97% MeCN over 3 min), MS (ESI+) m/z 316 (M+H)+.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH2:23])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([NH:23][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[N:20][C:19]=1[CH3:24])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)C1CCC1
Product: Cc1nc(NC(=O)C2CCC2)sc1C(=O)NCc1ccccc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclobutanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 46% yield; 1H NMR (DMSO-ds, 300 MHz) δ 7.38-7.25 (m, 4H), 5.96 (s, br, 1H), 4.58-4.50 (m, 2H), 3.25-3.14 (m, 1H), 2.53 (s, 3H), 2.42-1.90 (m, 6H); MS (ES+) m/z 330.0 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].[C:30](O)(=[O:33])[CH2:31][OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:33][CH2:30][C:31]([NH:29][CH:27]([CH3:28])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[N:17][C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[CH:13][CH:14]=2)=[CH:24][CH:23]=1)=[O:32]
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC(=O)CO

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (89 mg, 0.23 mmol) was reacted with glycolic acid and HATU in analogy to example 44. Yield: 40 mg (52%), M+H+: 359.19.
Reaction SMILES: [CH3:1][C@@H:2]1[O:19][C@@H:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][C@@:15]23O[C@@:3]12[C:4]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]3=[O:14])=[O:5].[OH-].[Na+]>>[CH3:1][CH:2]1[O:19][CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][C:15]2[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=3[C:4](=[O:5])[C:3]1=2)=[O:14]
Reactant: C[C@@H]1O[C@@H](CC(=O)O)C[C@@]23O[C@@]12C(=O)c1c(O)cccc1C3=O
Agent: [Na+]
Agent: [OH-]
Product: CC1OC(CC(=O)O)CC2=C1C(=O)c1c(O)cccc1C2=O

Procedure:
An aqueous solution of nanaomycin E (200 μg/ml) prepared in Example 1 was adjusted to a pH of 10 with addition of caustic soda. A reducing agent was added to the solution at a concentration of 3% by weight/volume, and the solution was kept at a temperature of 50° C. The change of the concentration of nanaomycin A formed in the solution was determined with the lapse of time. The production yield was determined at the end of the reaction. The results are shown in Table 1.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].[CH3:24][NH:25][CH3:26]>ClCCl>[CH3:24][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][CH2:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:23])[N:2]([CH3:1])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: Cn1c(-c2ccccc2)c(CCC(=O)O)c2ccccc2c1=O
Solvent: ClCCl
Product: CN(C)C(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 0.9 g (2.93 mmol) of 2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-propanoic acid in 150 ml of dichloromethane is prepared in a 500 ml round-bottomed flask placed under an argon atmosphere, 0.7 g (4.3 mmol) of N,N'-carbonyldiimidazole is added, the mixture is stirred at room temperature for 2 h, is saturated for 1 min with gaseous dimethylamine and stirring is continued for 12 h. The solvent is evaporated under reduced pressure, the residue is taken up in 200 ml of dichloromethane, 100 ml of water and 1M hydrochloric acid, the organic phase is separated, washed with water, dried over sodium sulphate and filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30 and then with a 95/5 mixture of dichloromethane and methanol. After recrystallizing from a mixture of dichloromethane, methanol and acetonitrile, 0.72 g (2.15 mmol) of white solid is obtained. Melting point: 165.5°-166° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cccc(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3cccc(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
(2S,4S)-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (77 mg, 0.23 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 2 mL, 11.42 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: Agilent, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(3-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (51.4 mg, 81%). 1H NMR (400 MHz, cd3od) δ 1.74-1.84 (m, 1H), 1.98-2.16 (m, 3H), 2.84-3.10 (m, 3H), 3.19-3.29 (m, 2H), 3.35-3.44 (m, 1H), 5.50 (s, 1H), 6.96-7.07 (m, 3H), 7.29-7.37 (m, 1H). HRMS Calculated for [C15H17FN2O2+H]+: 277.1352. Found: 277.1357
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[NH:14])[C:12]3[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[N:16][NH:17][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:13]2[N:14]=[CH:9][N:10]=[C:11]3[NH:17][N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[C:12]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 0 °C

Procedure:
A mixture of 0.9 g (2.45 mmol) of 5-(3-chloro-phenyl)-1,5-dihydro-4-imino-3-(3-methoxy-phenylamino)-4H-pyrazolo[3,4-d]pyrimidine, 18 ml of dioxane and 18 ml of water is heated under reflux for 10 hours. Cooling to 0° C., filtering and recrystallization from methanol/water and from methanol yield the title compound; m.p. 203-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(N2C(=O)C=C(CS(O)(=O)=O)N2)[CH:15]=CC=[CH:12][CH:11]=1>[Cr].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:9])[CH:3]=1.[OH:8][C:5]1[CH:6]=[CH:7][C:2]2[C:3](=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:4]=1
Reactant: O=c1cc(CS(=O)(=O)O)[nH]n1-c1ccccc1
Agent: [Cr]
Agent: Nc1cc(Cl)ccc1O
Solvent: O
Product: Oc1ccc2ccccc2c1

Procedure:
49.95 Parts of the 1:1 chromium complex (obtained by the known process and containing 1 atom of chromium for each molecule of monoazo dyestuff) of the azo dyestuff from diazotised 4-chloro-2-amino-1-hydroxybenzene and 1-phenyl-3-sulphomethyl-5-pyrazolone are stirred in 1000 parts of hot water together with 29.85 parts of the monoazo dyestuff obtained by the known process from diazotised 4-chloro-2-amino-1-hydroxybenzene and 2-hydroxynaphthalene. The suspension is adjusted to pH 7 to 8 by addition of 20 parts by volume of concentrated sodium hydroxide solution and subsequently stirred at 90°-95° C. until both starting dyestuffs can no longer be detected. The unitary chromium mixed complex present in clear solution is precipitated by the addition of sodium chloride, isolated by filtration, washed with sodium chloride solution, and then dried in vacuo. After it has been ground, the dyestuff is in the form of a dark red, readily water-soluble powder and from a bath containing ammonium sulphate dyes wool or polyamide fibres in full brown shades with good fastness properties. It has the following constitution: ##STR14##