Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[Br:12].[CH2:14]([OH:17])[CH2:15]O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:17][CH2:14][CH:15]=[CH:18][O:11]2)=[CH:6][C:5]=1[Br:12]
Reactant: COC(=O)c1ccc(C=O)cc1Br
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2OC=CCO2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 729.2 %

Procedure:
The mixture of 2-bromo-4-formyl-benzoic acid methyl ester (440 mg, 1.8 mmol), ethylene glycol (1.1 g, 18 mmol) and p-toluene sulfonic acid (30 mg) in THF (10 mL) is stirred at room temperature overnight. The reaction mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (380 mg, 73%). LC-ES/MS m/e 287.0 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[C:6](F)[CH:7]=1.[CH3:9][O-:10].[Na+].[CH3:12][OH:13]>>[CH3:9][O:10][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:13][CH3:12])[CH:7]=1
Reactant: Fc1cncc(F)c1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1cncc(OC)c1
Temperature: 135 °C
Yield: 57 %

Procedure:
To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.4 Hz, 2H), 6.76 (t, J=2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H+) m/z 140.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(F)c3c(c2)CCC(=O)N3C)c1
Temperature: 120 °C
Yield: 49.8 %

Procedure:
A mixture of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.6 mg, 0.0066 mmol) and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 min. The resulting reaction mixture was then diluted with EtOAc, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (12.4 mg, 50%) as a white solid. MS: 378.1 (M+H+)+.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[OH-:32].[Na+]>C1C=CC=CC=1>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[C:11]([Cl:15])[N:10]=[C:9]2[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][CH:4]=1)=[O:32]
Reactant: [OH-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5.05 g of 1-(4-cyanobenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 350 mL of benzene at 25° was added dropwise 22.8 mL of diisobutylaluminum hydride (0.15M in toluene). The mixture was warmed to 45° and stirred for 16 hours. After cooling, the reaction mixture was poured in ice-cold 20% aqueous sulfuric acid. This solution was allowed to warm to 25° and then stirred for 2 hours. The solution was cooled to 0°, neutralized using aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) provided 3.60 g of 1-(4-formyl-benzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3) δ: 9.96 (s, 1H); 7.47 (A2M2, 4H); 5.26 (s, 2H); 4.42 (s, 2H); 2.54 (t, 2H); 1.64 (quint., 2H); 1.32 (sext., 2H); 0.86 (t, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[O:105]=[C:106]1[CH:110]=[CH:109][C:108](=[O:111])[N:107]1[CH2:112][CH2:113][CH2:114][C:115]([N:117]([CH3:122])[CH2:118][CH2:119][NH:120][CH3:121])=[O:116]>CN(C=O)C>[O:105]=[C:106]1[CH:110]=[CH:109][C:108](=[O:111])[N:107]1[CH2:112][CH2:113][CH2:114][C:115]([N:117]([CH3:122])[CH2:118][CH2:119][N:120]([CH3:121])[C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:64])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:24]([O:58][CH3:59])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:56][CH3:57])[C@@H:34]([CH3:55])[C:35]([NH:37][C@@:38]1([C:47]([N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:48])[CH2:40][C@@H:39]1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:116]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: CNCCN(C)C(=O)CCCN1C(=O)C=CC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)CCN(C)C(=O)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.6 mg (7.3 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 2000 μl of DMF and then admixed with 5.6 mg (14.7 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2.6 μl of N,N-diisopropylethylamine and with 4.1 mg (9 μmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methyl-N-[2-(methylamino)ethyl]butanamide trifluoroacetate. After stirring at RT for 3 h, the same amounts of HATU and N,N-diisopropylethylamine were added once again, and the reaction mixture was then stirred at RT overnight. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. Thus, 4 mg (44% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:18].[C:30]([OH:37])(=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34]>CO>[CH3:1][O:2][C:3]1[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)=[C:5]2[C:10](=[C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=1)[N:9]=[C:8]([CH:31]([C:30]([OH:37])=[O:36])[CH2:32][C:33]([OH:35])=[O:34])[CH:7]=[C:6]2[CH3:18]
Reactant: COc1cc(NCCCN)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCC(=O)O
Solvent: CO
Product: COc1cc(NCCCN)c2nc(C(CC(=O)O)C(=O)O)cc(C)c2c1Oc1cccc(C(F)(F)F)c1

Procedure:
A solution of the above phthalimide 10 in 100 mL of 65% hydrazine and 100 mL of ethanol was refluxed under argon for 3 hours. After cooling to room temperature, the solution was diluted with 10% aqueous KOH solution and extracted with dichloromethane three times. The combined extract was washed with brine, dried (K2CO3), concentrated, and column chromatographed on silica gel using dichloromethane and methanol as eluants to give 1.86 g (80% yield) of 6-methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3-trifluoromethylphenyloxy)quinoline. 1H NMR (CDCl3) δ 8.40 (d, J=4 Hz, 1 H), 7.34 (t, J=8 Hz, 1 H), 7.21 (d, J=8 Hz, 1 H), 7.06 (m, 2 H), 6.93 (d, J=8 Hz, 1 H), 6.48 (s, 1 H), 6.4 (bs, 1 H, NH), 3.83 (s, 3 H, OMe), 3.42 (t, J=8 Hz, 2 H), 2.99 (t, J=8 Hz, 2 H), 2.62 (s, 3 H, Me), 1.98 (pentet, J=8 Hz, 2 H), 1.80 (bs, 2 H, NH2). 13C NMR (CDCl3) δ 160.0, 151.1, 145.0, 143.5, 142.7, 130.2, 125.2, 118.4, 118.2, 112.2, 107.5, 92.9, 56.8, 41.6, 40.4, 33.1, 23.4. The succinic acid salt was prepared by treating 0.457 g (1.12 mmol) of the quinoline with 0.134 g (1.13 mmol) of succinic acid in 10 mL of methanol. The resulting solution was concentrated to dryness, crystallized from diethyl ether to give a quantitative yield of the succinic acid salt PQ1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.N1C=CC=CC=1.O>C(#N)C>[Cl:23][C:13]1[CH:14]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:17]([Cl:18])[C:12]=1[N:11]1[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[C:8]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:9]=[N:10]1
Reactant: CCC(=O)Cl
Reactant: Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCC(=O)Nc1c(-n2cncn2)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Yield: 81.1 %

Procedure:
3.5 g (0.037 mole) of propionyl chloride are added dropwise to a solution of 7.3 g (0.02 mole) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(1,2,4-triazol-1-yl)-pyrazole and 2 g (0.025 mole) of pyridine in 60 ml of acetonitrile, with stirring, and, when the addition has ended, the mixture is stirred at room temperature for a further 12 to 15 hours. For working up, the reaction batch is poured into water and extracted with methylene chloride, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed in vacuo. The residue is dissolved in 100 ml of ethanol, 10 ml of aqueous ammonia are added, the mixture is heated to 50° C. for 15 minutes and concentrated in vacuo and the residue is triturated with water and dried on clay. 6.8 g (81% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-propionylamino-4-(1,2,4-triazol-1-yl)-pyrazole of melting point 167° C. to 169° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[S:13])[NH:8][C:7]1=[O:14].[C:19](=O)([O-])[O-].[K+].[K+].CI.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([OH:14])=[N:8][C:9]([S:13][CH3:19])=[N:10][C:11]=1[OH:12]
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1OC1C(=O)NC(=S)NC1=O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(O)nc(SC)nc1O
Reaction time: 4 h
Yield: 61.9 %

Procedure:
19.8 g 5-(o-methoxyphenoxy)-2-thioxo-dihydro-pyrimidine-4,6-dione was dissolved in 100 ml DMSO and 10.28 g potassium carbonate was added. After 30 min 4.36 ml methyl iodide was added in portions within 10 min. Stirring was continued for 4 h followed by the addition of 250 ml water. The solution was acidified with 25% hydrochloric acid. The precipitated product was filtered off, washed with diethylether and dried in vacuo to give 12.9 g 5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidine-4,6-diol. LC-MS: tR=3.01 min, [M−1]−=279.15.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>CS(C)=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1

Procedure:
A mixture of 10-[[6-chloro-3-pyridinyl]-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.2 g), K2CO3 (5 g) and the 2-dimethylaminoethylamine (5 ml) is heated in dimethylsulfoxide (80 ml) for 6 hours at 100° C. (with stirring). The reaction mixture is quenched with water and the solid which separates, is filtered off and washed well with water. Examination of the TLC (CHCl3 :MeOH; 3:1) showed the products to be sufficiently pure to be used for further reactions without purification. Yield 3.2 g, 85%, mass spectrum (CI) 376 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g, 1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in 30 mL dichloromethane and cool to 0° C. Treat the reaction mixture with benzoyl chloride (276 mg, 1.96 mmol) and stir overnight during which the temperature was allowed to warn to room temperature. Concentrate to residue and chromatograph the residue on silica gel eluting with 0.5% MeOH in CHCl3 to give the title compound as a solid: ISMS 410 (M+1); 1H NMR (CDCl3) 7.86-7.85 (m, 2H), 7.79 (s, 1H), 7.72-7.68 (m, 2H), 7.60-7.57 (m, 2H), 7.46-7.42 (m, 1H), 7.4-7.36 (m, 3H), 7.13-7.11 (d, 1H), 6.89-6.88 (m, 1H), 3.88-3.84 (t, 2H), 3.00-2.97 (t, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1C2C=CC=CC=2N=N1.N>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH2:52])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[CH:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: [Pd]
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COC1[C@@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(N)=O)c(O)c5C3(O)C4=O)C2=O)O[C@@H](C)[C@H](OC)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and ammonia (0.22 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((2S,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (12 mg, 15%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 12.89 (s, 1H), 8.22 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.96 (s, 2H), 5.87 (s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (s, 3H), 3.59-3.50 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (s, 3H), 1.36 (s, 3H); MS (ESI+) m/z 683 (M+H); HPLC 94.3% (AUC), tR 11.64 min.
Reaction SMILES: Cl.[C:2]([O:6][C@H:7]([CH3:19])[C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:24]([O:23][C:21]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[C@@H:7]([CH3:19])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C#N
Yield: 100 %

Procedure:
A solution of (2S)-1-(O′-tert-butylthreoninyl)pyrrolidine-2-carbonitrile hydrochloride (35 mg, 0.12 mmol; prepared according to Jenkins et al., WO95/15309), benzyl chloroformate (32 mg, 0.13 mmol) and triethylamine (24 mg, 0.24 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant: chloroform:methanol; 98:2) yielding a white solid identified as the title compound (47 mg, 0.12 mmol, 100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[CH:29])=[N:26][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:10]4[CH2:14][CH2:13][CH2:12][NH:11]4)=[CH:4][CH:3]=3)=[N:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(NC[C@@H]2CCCN2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NC[C@@H]4CCCN4)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from (4-iodophenyl)-(S)-1-pyrrolidin-2-ylmethylamine and 5-(4-chlorophenyl)-2-ethynylpyridine. The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). The eluates were evaporated down in vacuo and the residue was neutralized with sat. aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM, dried over magnesium sulfate and evaporated down in vacuo. Yield: 35 mg (11% of theoretical); C24H22ClN3 (M=387.904); calc.: molpeak (M+H)+:388/390 (Cl); found: molpeak (M+H)+:388/390 (Cl); HPLC-MS: 5.0 minutes (method B).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][NH:20][C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].ClCCl>CS(C)=O>[CH2:27]([N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1)[CH:26]=[CH2:25]
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(Br)cn3)cc1-2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCn1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (250 mg, 0.704 mmol) was dissolved in dimethylsulfoxide (3 mL) and treated with sodium hydride (70.4 mg, 1.76 mmol, 2.5 equiv) and allyl bromide (170 mg, 1.41 mmol, 2.0 equiv). The mixture was stirred at ambient temperature for 18 hours, poured into dichloromethane (50 mL) and washed with sodium bicarbonate (2×50 mL, aqueous saturated) and brine (1×50 mL). The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound: 1H-NMR (400 MHz, CD3OD) δ 8.90 (1H, s), 8.56 (1H, s), 8.34 (1H, d, J=9.0 Hz), 7.99 (1H, d, J=6.2 Hz), 7.74 (1H, d, J=8.2 Hz), 7.63-7.55 (2H, m), 7.42 (1H, d, J=8.4 Hz), 6.07-5.98 (1H, m), 5.81 (2H, s), 5.24-5.16 (2H, m), 4.86 (2H, s), ppm; low resolution mass spectrometry (ES+) m/z 396.8 (81Br) [(M+H)+; calculated for C19H15BrN4O: 397.0].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=C[CH:14]=[C:15]2NC(=O)OC(=O)[C:16]=12.[C:23]([OH:26])(=O)[CH3:24]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]2[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[NH:9][C:23](=[O:26])[C:24]=2[CH:12]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Product: Cc1ccc2c(c1)NC(=O)c1cc(Cl)ccc1N2
Temperature: 110 °C

Procedure:
A mixture of 4-methyl-1,2-phenylenediamine (0.1 mol) and 6-chloro isatoic anhydride (0.1 mol) in acetic acid (85%) was heated at 110° C. for 2 hrs. The mixture was poured into ice-cold water and 2-chloro-8-methyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-one was isolated (93%) after neutralisation and filtration.