Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>C(O)(=O)C>[CH:35]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[NH:18][C:17]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36]
Reactant: CCCCCCCCCCCc1cc2cc(C(=O)OC)ccc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCc1[nH]c2ccc(C(=O)OC)cc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (21.5 ml) in dimethylformamide (80 ml) was added to a solution of methyl 2-(n-undecyl)indole-5-carboxylate (36.9 g) in dimethylformamide (320 ml) and the mixture was stirred at a temperature of 60°-70° C. for 2 hours. After cooling the mixture was poured into water (500 ml). An aqueous solution of sodium hydroxide (50% w/v) was added to the mixture to adjust the pH to 12. Glacial acetic acid was then added to the stirred mixture to readjust the pH to 5. The resultant solid was collected and on recrystallisation from ethanol gave methyl 3-formyl-2-(n-undecyl)indole-5-carboxylate (34.8 g), m.p. 162°-165° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.CO>O.C(Cl)Cl.Cl[Pd]Cl>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(Cl)cc2Cl)c1
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Potassium carbonate (1.812 g, 13.11 mmol), methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2,4-dichlorophenylboronic acid (5.00 g, 26.23 mmol), PdCl2 (dppf) (0.380 g, 0.52 mmol), and MeOH (30.6 mL) were split in two 20 mL microwave vials and heated to 100° C. for 35 min in a single node microwave reactor. The reaction mixture was diluted with water and DCM, extracted with DCM and evaporated. Purified by automated flash chromatography using 5% EtOAc in heptane ->30% EtOAc over 15 CV at 280 nm. Methyl 2-(2,4-dichlorophenyl)isonicotinate (2.3 g, 47%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.37 (dd, 1H), 7.53 (d, 1H), 7.57 (d, 1H), 7.86 (dd, 1H), 8.20 (s, 1H), 8.87 (d, 1H). MS m/z 282 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][OH:16])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(NC(=O)CO)cc1
Reaction time: 10 h
Yield: 36.1 %

Procedure:
2-[4-(2-Benzyloxyacetylamino)-phenoxy]-propionic acid methyl ester 51 (15 gm, 43.7 mmol) was dissolved in methanol (150 ml) in a pressure vessel. Palladium on carbon (5%, 8 g) was added and the mixture stirred under a hydrogen atmosphere (2.5 kg) for 10 hrs. Catalyst was removed by filtration and the methanol distilled off. The crude 52 was recrystallised in chloroform:hexane (1:6) to give pure 52 (4 g, 36.3%) as a white powder with an m.p. between 111-112.6° C. IH NMR (CDCl3) δ 1.60 (d, 3H, CH3), 3.44 (bt, 1H, OH), 3.78 (s, 3H, Ester), 4.14 (d, 1H, CH2OH), 4.72 (q, 1H, CH), 6.80 (d, 2H, Ar), 7.44 (d, 2H, Ar), 8.30 (s, 1H, NH)
Reaction SMILES: [NH2:1][C:2]1[NH:3][SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:20]1([CH3:33])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:31]O)(=[O:30])=[O:29]>ClCCl>[C:20]1([CH3:33])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([OH:19])(=[O:30])=[O:29].[NH2:1][C:2]1[N:7]([NH2:31])[C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: NC1=Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Product: NC1=N[SH](=O)(c2ccccc2)c2cc(Cl)ccc2N1N
Reaction time: 1 h

Procedure:
To a suspension of 18.2 g of 3-amino-7-chloro-1-phenyl-1,2,4-benzothiadiazine-1-oxide in 75 ml dichloromethane is added slowly a solution of 16.1 g mesitylene sulfonylhydroxylamine (MSH) in 90 ml dichloromethane at 0° C. under stirring. Thereafter stirring is continued for one hour at room temperature and the precipitate then sucked off, washed with diethylether and air-dried. Colorless 3,4-diamino-7-chloro-1-phenyl-1,2,4-benzothiadiazine-1-oxide mesitylene sulfonate, m. pt. 225° C., are obtained. To 10.0 g thereof, suspended in 30 ml pyridine are added under stirring 8.3 g trifluoroacetic acid anhydride. After four hours of boiling the solvent is distilled in a water-jet pump vacuum. The residue is partitioned in dichloromethane/aqueous sodium bicarbonate. The organic layer is concentrated and the residue recrystallized from ethanol. A 3.9 g colorless solid product is obtained, m. pt. 167° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[NH:13][C:12]([CH3:18])([C:14](OC)=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][NH2:22]>CCO>[C:1]([O:5][C:6]([C@H:8]1[NH:13][C:12]([CH3:18])([C:14]([NH:21][NH2:22])=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(C)CC(=O)N(C)[C@@H](C(=O)OC(C)(C)C)N1
Reactant: NN
Solvent: CCO
Product: CN1C(=O)CC(C)(C(=O)NN)N[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.4 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate (0.074 g, 0.25 mmol) in EtOH (0.5 mL) was added NH2NH2 (0.023 mL, 0.75 mmol, 3 eq) and the mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo to give 0.074 g (100%) of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1, R6=Me) as a yellow solid. 1H NMR (CDCl3) δ 8.95 (s, 1H), 3.11 (s, 3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][NH2:9].[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][NH:9][CH:12]([CH3:13])[CH2:11][C:10]#[N:14]
Reactant: C/C=C/C#N
Reactant: NCCCC1OCCO1
Solvent: CCOC(C)=O
Product: CC(CC#N)NCCCC1OCCO1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
49.85 g (0.38 mol) of 3-[1,3]-dioxolan-2-yl-propylamine and 43.34 g (0.646 mol) of crotononitrile are combined in a 200 ml round-bottomed flask and heated at 100° C. for 72 hours. After cooling, the brown mass is diluted with ethyl acetate and washed with water. The organic phase is dried over calcium carbonate and purified by filtration on silica gel (eluent: ethyl acetate). Evaporation of the solvent gives 69.8 g of 3-(3-[1,3]-dioxolan-2-ylpropylamino)butyronitrile as a reddish liquid which is used without further purification in the next stage.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=c1cc(CO)occ1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COc2coc(CO)cc2=O)cc1

Procedure:
42.6 9 of kojic acid is dissolved in 350 ml of N-dimethylformamide, then 82.8 g of anhydrous potassium carbonate and 55 g of p-methoxybenzyl chloride are added thereto, and reacted at 70°-75° C. for 1.5 hours. After the reaction, the reaction mixture is concentrated to about half the volume, and added dropwise to 700 ml of water with ice cooling. The formed precipitates are filtered off, washed with water and ethyl acetate and dried to obtain 59.9 g of 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone.
Reaction SMILES: O=[C:2]([CH2:24][CH2:25][C:26](=O)[C:27]1[S:28][C:29]([CH2:32][O:33]C2CCCCO2)=[CH:30][N:31]=1)[CH:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C.C(OCC)(=O)C>[OH:33][CH2:32][C:29]1[S:28][C:27]([C:26]2[NH:45][C:2]([CH:3]([C:11]3[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=3)[CH2:4][CH:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:24][CH:25]=2)=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-[2,5-dioxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-5-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}pentyl]benzoate (2.24 g) in acetic acid (15 mL) was added ammonium acetate (4.85 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was m washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.30 g, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 469 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[O:35]([CH2:42][C:43](Cl)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:43](=[O:44])[CH2:42][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCN(C(=O)COc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (34 mg) which was characterized by its mass spectrum: MS m/z (%): 493 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[CH:4][C:3]=1[CH3:16].[CH:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(OCC)(=O)C.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.COCCOC>[CH2:14]([O:13][CH2:12][CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH3:16])[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:17]=[O:18])[CH:24]=2)=[C:7]([CH3:8])[C:6]=1[CH3:9])[CH3:15]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1C
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1C
Temperature: 90 °C
Reaction time: 64 h
Yield: 27.7 %

Procedure:
A mixture of 2-bromo-5-(2-ethoxyethoxy)-1,3,4-trimethylbenzene (1.16 g, 4.04 mmol), 3-formylphenylboronic acid (0.67 g, 4.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol), cesium carbonate (3.2 g, 9.7 mmol), water (4.8 mL) and 1,2-dimethoxyethane (15 mL) was stirred under a nitrogen atmosphere at 90° C. for 64 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.35 g, yield 28%) as a colorless oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH2:32][CH3:33].ClCCl>N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([CH2:30][CH2:31][CH2:32][CH3:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzenesulfonyl chloride (0.45 ml in 10 ml dichloromethane, 3.5 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol), dichloromethane (140 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for four hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol, Rf 0.28) followed by recrystallization from dichloromethane\diethyl ether to provide 1.14 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzenesulfonamide as a white powder, m.p. 75.5-79.0° C. 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.2, 2H), 7.63-7.53 (m, 5H), 7.42 (m, 1H), 7.25 (m, 1H), 6.43 (broad s, 2H), 4.45 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H), 2.78 (m, 2H), 1.79 (m, 4H), 1.55-1.40 (m, 4H), 0.95 (t, J=7.4 Hz, 3H); MS (EI) m/e 451.2036 (451.2042 calcd for C24H29N5O2S); Anal calcd for C24H29N5O2S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.89; H, 6.42; N, 15.30.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=2)[N:7]=1.O.O.[Sn](Cl)Cl.[CH3:22][C:23]([CH3:30])([CH3:29])[C:24](=O)[CH2:25][C:26]#[N:27]>O.Cl.CCOCC.C(O)C>[C:23]([C:24]1[CH:25]=[C:26]([NH2:27])[N:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[C:6]([CH3:5])[CH:15]=[CH:14]3)[N:1]=1)([CH3:30])([CH3:29])[CH3:22]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc2cc(-n3nc(C(C)(C)C)cc3N)ccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A solution of sodium nitrite (502 mg, 7.27 mmol) in H2O (8 ml) was added dropwise to a well-stirred 0° C. mixture of 2-methylquinolin-6-amine (1.00 g, 6.32 mmol) in conc. HCl (10 ml). The resulting mixture was stirred at 0° C. for 1 h. Tin(II) chloride dihydrate (6.13 g, 27.2 mmol) in conc. HCl (8 ml) was added and stirring was continued at 0° C. for 1 h and then RT for 2 h. Ethanol (60 ml) and 4,4-dimethyl-3-oxopentanenitrile (1.03 g, 8.22 mmol) were added and the mixture was heated at reflux overnight. The completed reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 mL). The mixture was cooled in an ice/water bath and made basic (pH˜8) with solid sodium hydroxide. The solution was filtered through Celite, and the filter cake was washed with water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine, dried (Na2SO4), and concentrated to yield a foam. The foam was stirred in ether (50 mL) and allowed to stand for several hours. The resultant solid was collected by filtration and dried in vacuo to yield 3-tert-butyl-1-(2-methylquinolin-6-yl)-1H-pyrazol-5-amine (428 mg, 24% yield). MS (ESI) m/z: 281.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[F:20][C:21]([F:38])([F:37])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.FC(F)(F)C1C=CC(C2C(C(O)=O)=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:34]([C:29]2[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:37])[F:38])=[CH:23][CH:24]=3)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:35])=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminobenzoic acid ethyl ester (0.568 g) and triethylamine (0.570 g) were dissolved in methylene chloride (20 mL), and to this solution was dropwise added a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride, which is prepared from 4′-trifluoromethylbiphenyl-2-carboxylic acid (1.00 g) in a similar manner to Example 1d), in methylene chloride under ice-cooling. The solution was stirred at room temperature for 2 hours, followed by addition of methylene chloride (100 mL). The reaction mixture was washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated to give the title compound (1.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:11]3[C:22]([OH:23])=[C:21]4[C:16]([CH2:17][C@@:18]([OH:29])([C:25]([CH2:27]Br)=[O:26])[CH2:19][C@@H:20]4[OH:24])=[C:15]([OH:30])[C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:10].C(Cl)(Cl)Cl.[OH-:35].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:11]3[C:22]([OH:23])=[C:21]4[C:16]([CH2:17][C@@:18]([OH:29])([C:25]([CH2:27][OH:35])=[O:26])[CH2:19][C@@H:20]4[OH:24])=[C:15]([OH:30])[C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: [OH-]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CBr)C[C@@H]3O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O

Procedure:
In order to introduce a hydroxyl group at the 14- position of compound (IX), said position is first provided with a bromine atom in conventional bromination step (Br2, CHCl3, 23°, 16 hrs). The 14-bromodaunomycinone (X), after being freed of CHCl3, is dissolved in aqueous acetone and subjected to hydrolysis with NaOH (1.1 eq, reflux 5 mins) to afford adriamycinone (XI) which is recovered after water workup and extraction with CHCl3 /MeOH. This portion of the process forms the subject of Example 7. ##STR4##
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:4]1.[N-:29]=[N+:30]=[N-:31].[Na+]>O.CN(C=O)C.CC(=O)OCC.O>[N:29]([C@H:7]1[C@@H:3]([O:2][CH3:1])[CH2:4][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6]1)=[N+:30]=[N-:31]
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 89.8 %

Procedure:
(+/−)-Trans-benzyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate (10.3 g, 25.4 mmol) was added to the soln. of sodium azide (5.78 g, 89 mmol) in water (10 mL) and DMF (60 mL) and heated to 100 deg. Celsius overnight. Diluted with EA/water and stirred. The organic layer dried (Na2SO4) and concentrated to give (+/−)-Cis-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (6.3 g, 22.80 mmol, 90% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.34-7.43 (5 H, m), 5.13-5.21 (2 H, m), 4.01-4.04 (2 H, m), 3.47 (3 H, s), 3.49-3.69 (4 H, m), Hz), LCMS: M+23=299, Rt=2.15 min.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:28])[C@H:4]([CH2:21]C1C=CC=CC=1)[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH2:14])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>>[CH3:1][NH:2][C:3](=[O:28])[CH:4]([CH3:21])[NH:5][C:6](=[O:20])[C:7]1[C:12]([I:13])=[C:11]([NH:14][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:10]([I:15])=[C:9]([C:16]([OH:18])=[O:17])[C:8]=1[I:19]
Reactant: COCC(=O)Cl
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Product: CNC(=O)C(C)NC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I

Procedure:
This compound is obtained as described in Example 11 from N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-DL-alanine methylamide (IV d), m.p. 208°-209° C. (under decomposition), and methoxyacetyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1C1C=CC=CC=1.[I:30]C1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=C(O)C=CC=1I>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:30])=[C:6]([CH:7]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Agent: NCc1cc(O)ccc1I
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1cc(O)ccc1I
Yield: 73 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.30 mmol) and 3-Aminomethyl-4-iodo-phenol (80 mg, 0.32 mmol) in 73% yield: MS (ESI): 545.0 (M−1)−1.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:16][C:17]1[N:18]=[C:19]([NH:13][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH3:12])[CH:20]=[N:21][CH:22]=1
Reactant: CCCC(N)c1ccc(C(F)(F)F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(Nc1cncc(Cl)n1)c1ccc(C)cc1
Temperature: 25 °C
Yield: 5.7 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-amine (0.40 g, 1.9 mmol) and 2,6-dichloropyrazine (0.55 g, 3.7 mmol) in 1,4-dioxane (6 mL) was added anhydrous potassium carbonate (0.39 g, 2.8 mmol). The resulting mixture was heated at reflux for 18 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and H2O. The organic phase was collected, dried and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (0.03 g, 5%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)[O:41]CC.NC1C=C(O)C=CC=1>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[C:3]([OH:41])[CH:2]=3)[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1-c1cccc(O)c1
Yield: 38.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.72 ml), 3-aminophenol (64.6 mg, 0.59 mmol), and acetic acid (0.09 ml) were used to give 41.5 mg (0.12 mmol, 38.3% yield) of the title compound.