Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH3:9])=[CH:3][CH:4]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-aminophenol (3.27 g, 30.0 mmol) in dichloromethane (50 ml) were added 3,3-dimethyl-butyryl chloride (8.08 g, 60.0 mmol) and pyridine (4.85 ml, 60.0 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 35 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material was collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (3.37 g) in methanol (50 ml) was added. After stirring for 2 days at room temperature water (300 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The solids were collected by filtration and dried under vacuum at 40° C. yielding the title compound (1.97 g, 31%, pink solid). The mother liquor was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with saturated sodium bicarbonate (2×250 ml), dried in vacuo, filtered and evaporated yielding a second amount of the title compound (0.67 g, 10%). From the first aqueous extract another portion of product was isolated by extraction with ethyl acetate (4×250 ml). The combined organic phases were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a third amount of the title compound (2.11 g, 34%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[CH2:4].[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[CH2:4])=[O:13]
Reactant: C=C[C@@H](N)Cc1ccccc1
Reactant: CCOC=O
Product: C=C[C@H](Cc1ccccc1)NC=O

Procedure:
(S)-3-Amino-4-phenyl-1-butene (5.2 g, 35.4 mmol) was dissolved in ethyl formate (100 ml) and the solution was refluxed with heat for 6 hours. After completion of reaction, the solution was concentrated under reduced pressure to give the desired compound as an orange oil. Yield: 6.44 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:4][N:3]=1
Reactant: ClCc1ccsc1
Reactant: Oc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OCc2ccsc2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 2-chloro-5-hydroxypyrimidine (200 mg), 3-chloromethylthiophene (610 mg), potassium carbonate (635 mg) and dimethylformamide (3 ml) is stirred at 50° C. for one hour. After the reaction is complete, to the reaction mixture is added water, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=20:1→20:3), and evaporated to remove the solvent to give 2-chloro-5-(3-thienylmethoxy)pyrimidine (345 mg) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27]O)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:26]([CH2:27][C:31]#[N:33])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:29][CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a mixture of [2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (2.00 g), triethylamine (0.97 g) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (1.10 g) under ice-cooling and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.59 g) at room temperature and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crystals were subjected to silica gel column chromatography to give crystals (1.40 g, 68%) of 2-[2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: C(OC([N:8]1[CH2:20][C:19]2[S:18][C:17]3[N:16]=[C:15]([CH3:21])[C:14]([C:22](=[O:24])[CH3:23])=[C:13]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C:15]1[C:14]([C:22](=[O:24])[CH3:23])=[C:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:20][C:19]=3[S:18][C:17]=2[N:16]=1
Reactant: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCN(C(=O)OC(C)(C)C)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCNC3
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of 70 mg (0.16 mmol) 3-acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid tert-butyl ester in 3 ml dicloromethane was added 0.2 ml trifluoroacetic acid. The mixture was stirred over night at RT, and then poured onto an aqueous solution of NaHCO3, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 48 mg (94%) 1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[C:23]=[CH:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)CC=CC4)s3)c2n1
Agent: NS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)C=C=CC4)s3)c2n1
Temperature: 40 °C
Yield: 58.3 %

Procedure:
A mixture of 1-[5-(2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)thiophen-2-yl]cyclopenten-3-ene carboxylic acid (Example 3) (500 mg, 1.27 mmol) and 1,1-carbonyl diimidazole (250 mg, 1.27 mmol) in THF (25 ml) was heated under reflux for 3 hours, then a solution of benzenesulfonamide (242 mg, 1.6 mmol) and DBU (243 mg, 1.6 mmol) in THF (2.0 ml) was added. The reaction mixture was heated at 40° C. for 19 hours, cooled to 23° C. and concentrated in vacuo. The residue was dissolved in water and acidified with 10% aqueous NaH2PO3. The aqueous mixture was extracted with EtOAc (3×25 ml). The combined extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO2 gel using 2% MeOH/EtOAc to give 406 mg of the title compound (60% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[OH2:25].S(=O)(=O)(O)O.[CH3:31]O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[CH2:31][OH:25]
Reactant: O
Reactant: CO
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(CO)c2cc(F)ccc2n1
Yield: 81 %

Procedure:
To a solution of 10.0 g (62.0 mmol) of 6-fluoro-2-methylquinoline and 28.3 g (124.0 mmol) of ammonium peroxodisulfate in a mixture of methanol (140 mL)-water (110 mL) was added 4.0 mL of concentrated sulfuric acid, and heated under reflux for 18 hours. The reaction mixture was left to cool, and methanol was removed under a reduced pressure. The residue was adjusted to pH 10 by adding sodium carbonate, and then extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed to obtain 9.61 g (yield 81%) of (6-fluoro-2-methylquinolin-4-yl)methanol. Its physical properties are shown below.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16](=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO[CH:36](OC)[N:37]([CH3:39])[CH3:38].N1CC[CH2:44][CH2:43]1>CN(C)C=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:27])[C:10](=[CH:39][N:37]2[CH2:36][CH2:44][CH2:43][CH2:38]2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16](=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:15][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Reactant: O=C(CCCN1CCC(=Cc2ccccc2F)CC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C(=CN1CCCC1)CCN1CCC(=Cc2ccccc2F)CC1)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1.96 g of 1-[4-(4-fluorophenyl)-4-oxobutyl]-4-(2-fluorobenzylidene)piperidine hydrochloride, 345 mg of anhydrous potassium carbonate, 5.0 ml of N,N-dimethylformamide dimethylacetal, 3.5 ml of pyrrolidine and 5.0 ml of N,N-dimethylformamide was stirred on an oil bath at 120° C. for 2.5 hours. The reaction solution was separated with ethyl acetate and water, and the organic layer was concentrated under reduced pressure to give a crude 1-[4-(4-fluorophenyl)-4-oxo-3-pyrrolidinomethylenebutyl]-4-(2-fluorobenzylidene)piperidine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([S:16](Cl)(=[O:18])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C(Cl)Cl>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][S:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:18])=[O:17]
Reactant: CN(C)CCN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)C1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (110 mg, 0.362 mmol) in CH2Cl2 (1.5 mL) was added to a solution of N,N-dimethylethylenediamine (0.20 mL, 1.83 mmol) in CH2Cl2 (1 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, and then warmed to room temperature and stirred for 1 hr. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum to give benzyl 3-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-pyrrolidinecarboxylate (102 mg, 88%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.8 Hz, 2H), 3.80-3.72 (m, 4H), 3.50 (m, 1H), 3.16 (br s, 2H), 2.42 (t, J=5.7 Hz, 2H), 2.31 (m, 2H), 2.21 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.N1CCCCC1>C(O)C>[SH:7][C:4]1[S:3][C:2]2=[N:1][C:10]([CH3:12])=[CH:9][C:8](=[O:13])[N:6]2[N:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnc(S)s1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(=O)n2nc(S)sc2n1
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-5-mercapto-l,3,4-thiadiazole (4.0 g) and ethyl acetoacetate (4.3 g) in 50 ml ethanol, piperidine (2.55 g) was slowly added. The mixture was refluxed for seven hours and then allowed to stand overnight at room temperature. The formed crystals were collected by filtration and dissolved in 100 ml of water. The pH was adjusted to 2.0, and the formed crystals were collected and washed with 20 ml of water, affording 3.8 g of the objective compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:25])(=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>O1CCOCC1.O>[C:20]([N:18]([CH3:19])[S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)(=[O:25])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)N(C)C(C)(C)C)cc2)cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Procedure T′: A 15 mL dioxane/H2O (2:1) mixture of 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid methyl ester (318 mg, 0.88 mmol) and LiOH—H2O (46 mg, 1.1 mmol) is stirred at room temperature overnight. The reaction mixture is concentrated, is diluted with EtOAc, shaken with 1 NHCl, and the layers are separated. The 1 N HCl layer is extracted with EtOAc and the combined organic layers are washed with brine, then dried over Na2SO4 and evaporated to give the intermediate 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid (270 mg, 88% yield). MS (ES−) 346.1 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2Cl.CC(O)C.S(=O)(=O)(O)O>O.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2[NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: Clc1cnc2c(Cl)nccc2c1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@](CF)(c2cc(Nc3nccc4cc(Cl)cnc34)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 55 °C
Reaction time: 16 h
Yield: 24.85 %

Procedure:
A sealable vial was charged with crude (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (345 mg, 1.116 mmol, step 1) and 3,8-dichloro-1,7-naphthyridine (Intermediate 2; 233 mg, 1.171 mmol). iPrOH (8 mL) was added and the suspension was briefly sonicated. Sulfuric acid (0.059 mL, 1.116 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 55° C. in an oil bath for one hour then cooled to RT and stirred for additional 16 hours. The reaction was diluted with water and EtOAc. The aqueous layer separated was basified to pH=12 by the addition of 1N NaOH. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel chromatography using a gradient of 0-50% EtOAc:Hexanes to afford the title compound as a white solid. (130.8 mg, 0.277 mmol, 24.85% yield). MS m/z=472.0 [M+H]+. Calculated for C20H15ClF5N5O: 471.811
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[N:25]([CH3:26])[C:24](=[O:27])[C@H:23]([CH2:28][CH2:29][CH2:30][NH:31]C(=O)OCC2C=CC=CC=2)[NH:22][C:21](=[O:42])[C@@H:20]([NH:43]C(OCC2C=CC=CC=2)=O)[CH2:19][C:18]2[CH:54]=[C:14]([CH:15]=[CH:16][C:17]=2[O:55]CC2C=CC=CC=2)[C:13]2=[CH:63][C:9](=[C:10]([F:64])[CH:11]=[CH:12]2)[CH2:8]1)=[O:6]>[Pd].C(O)(=O)C.O.C(O)C>[NH2:43][C@H:20]1[CH2:19][C:18]2[CH:54]=[C:14]([CH:15]=[CH:16][C:17]=2[OH:55])[C:13]2=[CH:63][C:9](=[C:10]([F:64])[CH:11]=[CH:12]2)[CH2:8][C@@H:7]([C:5]([NH:4][CH2:3][CH2:2][NH2:1])=[O:6])[N:25]([CH3:26])[C:24](=[O:27])[C@H:23]([CH2:28][CH2:29][CH2:30][NH2:31])[NH:22][C:21]1=[O:42]
Reactant: CN1C(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C(=O)[C@H](CCCN)NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(F)c(c2)C[C@H]1C(=O)NCCN
Reaction time: 15 h

Procedure:
25 mg (0.029 mmol) of benzyl {3-[(8S,11S,14S)-8-{[(2-aminoethyl)amino]carbonyl}-17-(benzyloxy)-14-{[(benzyloxy)carbonyl]-amino}-5-fluoro-9-methyl-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-11-yl]pro-pyl}carbamate (Example 30O) are added into a mixture of 5 ml of acetic acid/water/ethanol (4:1:1) mixture. 10 mg of palladium on activated carbon (10%) are added, and the mixture is hydrogenated under atmospheric pressure at RT for 15 h. The reaction mixture is filtered through prewashed kieselguhr, washed with ethanol, and the filtrate is concentrated in vacuo on a rotary evaporator. The residue is mixed with 0.1N hydrochloric acid and concentrated in vacuo. The remaining solid is dried under high vacuum. The trihydrochloride is converted into the tri(hydrotrifluoroacetate) by preparative HPLC (Kromasil 100C18, mobile phase acetonitrile/0.2% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[CH:16][CH:15]=3.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:26])[C:10](=[O:11])[O:9][C:8]2[CH:12]=[CH:13][C:14]3[C:19]([C:7]1=2)=[CH:18][C:17]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:16]([N+:1]([O-:4])=[O:2])[CH:15]=3
Reactant: O=[N+]([O-])O
Reactant: CC1(C)C(=O)Oc2ccc3ccc(Cn4cncn4)cc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C(=O)Oc2ccc3cc([N+](=O)[O-])c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Nitric acid (72% by weight, 0.045 ml) was added dropwise to a stirred, ice-cooled mixture of 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone (0.44 g) and acetic anhydride (6 ml). The mixture was stirred at room temperature for 18 h, then added to a stirred mixture of aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash chromatography. Elution with ethyl acetate:pentane, 3:1 v/v, gave 1,1-dimethyl-7-nitro-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 183°-185° after recrystallisation from ethyl acetate. (Example 13).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH:29]4[CH2:31][CH:26]3[CH2:27][CH2:28]4)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[O:5][C:6]1C=CC=CC=1)#[N:2].[Cl:32][C:33]1[N:34]=[C:35]([NH:43][NH2:44])[C:36]2[S:41][CH:40]=[C:39]([CH3:42])[C:37]=2[N:38]=1.CN1C(=[O:51])CCC1>>[CH:6]([OH:5])=[O:51].[C@@H:26]12[CH2:31][C@@H:29]([CH2:28][CH2:27]1)[CH2:30][C@@H:25]2[N:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:4]3[N:3]=[C:1]([NH2:2])[N:43]([C:35]4[C:36]5[S:41][CH:40]=[C:39]([CH3:42])[C:37]=5[N:38]=[C:33]([Cl:32])[N:34]=4)[N:44]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: CN1CCCC1=O
Reactant: Cc1csc2c(NN)nc(Cl)nc12
Reactant: N#CNC(=Nc1ccc(N2CCN(C3CC4CCC3C4)CC2)cc1)Oc1ccccc1
Product: Cc1csc2c(-n3nc(Nc4ccc(N5CCN([C@H]6C[C@@H]7CC[C@H]6C7)CC5)cc4)nc3N)nc(Cl)nc12
Product: O=CO
Temperature: 180 °C
Yield: 31 %

Procedure:
A mixture of N-cyano-N′-{4-[4-(bicyclo[2.2.1]hept-2-yl)-1-piperazinyl]phenyl}-O-phenylisourea (50 mg; 0.12 mmol; 1.0 equiv) and 2-chloro-4-hydrazino-7-methylthieno[3,2-d]pyrimidine (26 mg; 0.12 mmol; 1 equiv) in 0.5 mL of NMP was heated in the microwave apparatus at 180° C. for 6 min. Purification by HPLC gave N3-(4-(4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-1H-1,2,4-triazole-3,5-diamine formic acid, compound #139, as a yellow solid (20 mg; 31% yield); 1H-NMR (DMSO-d6, 300 MHz) 9.20 (br. s, 1H), 8.21 (s, 1H), 7.90 (br. s, 2H), 7.56 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hs, 2H), 3.10-3.02 (m, 4H), 2.45-2.40 (m, 4H), 2.30-2.15 (m, 3H), 1.78-1.62 (m, 2H), 1.50-1.40 (m, 1H), 1.37-1.14 (m, 4H), 0.90-0.86 (m, 1H) ppm; MS (ES) 536.19 (M+H), 534.26 (M−H).
Reaction SMILES: [CH3:1][CH:2]([CH:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH3:32])[S:30][CH:31]=1.[Cl-].[NH4+:34]>CN(C=O)C.CCOCC>[CH3:32][C:29]1[S:30][CH:31]=[C:27]([CH2:26][O:22][C:17]2[CH:16]=[C:15]([CH2:14][C@@H:12]([CH3:13])[C@@H:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH2:26][C:27]4[N:28]=[C:29]([CH3:32])[S:30][CH:31]=4)=[C:6]([O:11][CH2:26][C:27]4[N:28]=[C:29]([CH3:32])[S:30][CH:31]=4)[CH:5]=3)[CH:20]=[CH:19][C:18]=2[O:21][CH2:26][C:27]2[N:34]=[C:29]([CH3:32])[S:30][CH:31]=2)[N:28]=1
Reactant: Cc1nc(CCl)cs1
Reactant: [NH4+]
Reactant: CC(Cc1ccc(O)c(O)c1)C(C)Cc1ccc(O)c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1nc(COc2ccc(C[C@@H](C)[C@@H](C)Cc3ccc(OCc4csc(C)n4)c(OCc4csc(C)n4)c3)cc2OCc2csc(C)n2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.09 %

Procedure:
To an ice-cooled solution of NDGA (1.50 g, 4.96 mol) in DMF (50 mL) was added 60% suspension of sodium hydride in paraffin (1.98 g=1.19 g NaH, 49.6 mmol, 10 mole equiv.). The mixture was stirred at 0° C. for 30 min. and at room temperature for 30 min. Then a solution of 4-chloromethyl-2-methylthiazole (5.86 g, 39.69 mmol, 8.0 mole equiv.) in DMF (20 mL) was added and the reaction mixture was allowed to stir for 16 h at room temperature. The reaction mixture was added to the saturated aqueous ammonium chloride (300 mL) and ether (600 mL). After shaking, the organic layer was separated, and the aqueous layer was extracted with ether (2×200 mL). The combined organic layer and extracts were washed with water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate and concentrated to dryness under reduced vacuum (30-40 mm Hg) at 25° C. The residue was dissolved in a minimum amount of dichloromethane and purified by silica gel flash chromatographic column using hexane:ethyl acetate (50:50 to 0:100) as eluant to give expected product as white solid (1.56 g, 42.09% yield). It was further purified by crystallization from acetate-hexane.