Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(C[O:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[C:12](F)[CH:11]=2)=CC=1.[F:34]C(F)(F)C1C=CC(COC(=O)C2C=CC(OCC3C=CC(F)=CC=3)=C(F)C=2)=CC=1>>[F:34][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:9]([OH:8])=[O:29]
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccc(C(F)(F)F)cc2)c(F)c1
Product: O=C(O)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1F
Yield: 90 %

Procedure:
As described for example 18b, 3-fluoro-4-(4-trifluoromethyl-benzyloxy)-benzoic acid 4-trifluoromethyl-benzyl ester (5.3 g, 11 mmol) [instead of 3-fluoro-4-(4-fluoro-benzyloxy)-benzoic acid 4-trifluoromethyl-benzyl ester] was converted to the title compound (3.1 g, 90%) which was obtained as a white solid. MS: m/e=312.9 (M−H−).
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20].[H-].[Na+]>C1COCC1>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][CH2:18][C:19](=[O:20])[NH:8][C:9]=2[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 0° C. for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 0° C. and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3×50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid. δH (DMSO-d6) 10.81 (1H, br. s), 7.08 (1H, dd, J 8.5 Hz and J 2.3 Hz), 7.02 (1H, d, J 2.3 Hz), 6.92 (1H, d, J 8.5 Hz), 4.60 (2H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl.CCN(CC)CC>[C:31]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 11 mg acetic acid anhydride were added at RT and stirred over night. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][NH:3][C:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:5]=1
Reactant: O=CNC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CNC1=NN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Formamido-1-(3-trifluoromethylphenyl)-2-pyrazoline (2.4 g) was stirred with dry diethyl ether (60 ml) to produce a slurry which was gradually added to a stirred ice-cold suspension of lithium aluminium hydride (1.0 g) in dry diethyl ether (75 ml) under a nitrogen atmosphere. The addition took place over a period of about 20 minutes and was accompanied by a vigorous reaction. The final reaction mixture was stirred for a further 15 minutes and was then carefully and slowly decomposed by the addition of water (30 ml). The ethereal layer was then decanted off the aqueous sludge which was washed twice with diethyl ether. The combined ethereal solutions were dried over potassium carbonate, filtered and evaporated. The resulting 3-methylamino-1-(3-trifluoromethylphenyl)-2-pyrazoline was a colourless crystalline solid on precipitation by benzene and recrystallization with light petroleum, yield 1.8 g, m.p. 93.1°. The hydrochloride was recrystallized by precipitation from methanol with ether and light petroleum m.p. 206°-207°.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=O)[CH3:2].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(C)=O>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)=[CH2:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: C=Cc1ccc2c(c1)[nH]c1ccccc12

Procedure:
The monomer of this polymer is synthesized in accord with the procedures described by Hyde, Kricke and Ledwith in Polymers 14, 124 (1973). According to their method, a mixture of 24 grams 2-acetyl carbazole and 40 gram aluminum isopropoxide in 75 milliliters of xylene is heated to boiling under reflux conditions. Such heating is continued for three hours, during which time acetone forms within the mixture and is removed therefrom by distillation. Upon cooling, particulates (principally aluminum isopropoxide) are removed from the mixture by filtration and the filtrate collected in water. Upon standing, the xylene and aqueous layers separate, whereupon the xylene is drawn off and the aqueous layer subsequently extracted with three 60 milliliter portions of ether. The combined extracts are washed with water and dried over anhydrous magnesium sulfate (MgSO4 /NaOH). Evaporation of the ether yields 2-vinylcarbazole monomer.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:21]=[CH:20][C:14]2[C:15]([CH2:18]O)=[CH:16][O:17][C:13]=2[CH:12]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:18][C:15]1[C:14]2[CH:20]=[CH:21][C:11]([O:10][C:2]3[S:1][C:9]4[C:4]([N:3]=3)=[N:5][CH:6]=[CH:7][CH:8]=4)=[CH:12][C:13]=2[O:17][CH:16]=1
Reactant: OCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-methanol (1.0 g, 3.4 mmol) in DCM (34 mL) was added SOCl2 (0.49 mL, 0.83 g, 7.0 mmol) and the reaction mixture was stirred (rt, 2 h). The reaction mixture was filtered to afford the hydrochloride salt of the title compound as a yellow solid (1.0 g, 84%). MS (ESI): mass calcd. for C15H9ClN2O2S, 316.01; m/z found, 317.0 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.93 (dd, J=8.1, 1.4, 1H), 8.69 (dd, J=5.9, 1.4, 1H), 8.02 (s, 1H), 7.90 (d, J=8.5, 1H), 7.81-7.75 (m, 2H), 7.45 (dd, J=8.5, 2.2, 1H), 4.90 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6](O)[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][CH:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[CH2:5][CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CC1c2ccccc2CC(O)Cc2ccccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1c2ccccc2C=CCc2ccccc21
Temperature: 0 °C

Procedure:
12-Methyl-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-ol (2.7 g., 0.011 mole) in 50 ml. of pyridine was treated with 15 ml. of phosphorous oxychloride. The mixture was heated at reflux for 45 minutes, cooled, and poured carefully into 600 ml. of stirred ice water. The resulting mixture was extracted three times with ether, and the combined ether layers were washed once with water, once with 1 N hydrochloric acid, and twice with water. The washed ether solution was dried over potassium carbonate, filtered, and evaporated in vacuo to give 1.9 g. of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])(=[O:21])=[O:20])[CH2:16][CH:15]2[C:32]([O:34]CC)=[O:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:29])([F:30])[F:31])(=[O:21])=[O:20])[CH2:16][CH:15]2[C:32]([OH:34])=[O:33])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(N2CC(S(=O)(=O)c3ccccc3C(F)(F)F)CC2C(=O)O)CC1

Procedure:
In analogy to the procedure described in example 253e, 4-[2-ethoxycarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=507.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:24][CH2:25][C@@H:26]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:17][C:7]2=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO.O>[NH2:31][C@@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:25][O:24][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-c3ccccn3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(-c3ccccn3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-(pyridin-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (35 mg, 0.068 mmol) in Methanol (4 mL) was added HCl in 1,4-dioxane (0.169 mL, 0.677 mmol) at 0° C. Then the reaction mixture was stirred at RT for 2 h. The volatiles were concentrated under reduced pressure. The residue so obtained was basified with saturated aqueous NaHCO3, diluted with water and extracted with DCM (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by reverse phase prep HPLC (Sunfire C18 column (19.0×150 mm) 10.0 micron; mobile phase A: 10 mM ammonium acetate in water; mobile phase B: acetonitrile; flow rate: 16.0 mL) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-9-(pyridin-2-yl)benzo[c][2,7]naphthyridin-5(6H)-one (10 mg, 0.024 mmol, 35% yield) as an off-white solid. LC/MS (ESI) m/e 417.6 [(M+H)+, calcd for C25H29N4O2 417.2]; LC/MS retention time (method E): tR=0.84 min; HPLC retention time (method A): tR=7.61 min; HPLC retention time (method B): tR=8.29 min; 1H NMR (400 MHz, METHANOL-d4). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.70 (d, J=4.3 Hz, 1H), 8.64 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 8.04-7.94 (m, 1H), 7.93-7.86 (m, 1H), 7.46 (ddd, J=7.3, 5.0, 1.3 Hz, 1H), 7.18 (s, 1H), 4.32 (dd, J=9.5, 4.3 Hz, 1H), 4.13 (dd, J=9.4, 6.7 Hz, 1H), 3.84 (s, 3H), 3.36-3.34 (m, 1H), 3.11 (s, 3H), 1.86-1.70 (m, 1H), 1.53-1.32 (m, 2H), 0.97 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: O[C:2]1[C:6](O)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=2)[N:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:4][C:3]=1[OH:37]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH2:14]([O:13][C:9]1[CH:8]=[C:7]([C:6]2[N:5]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:4]=[C:3]([OH:37])[CH:2]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCOc1cccc(C2(O)C(O)=C(O)NN2c2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cccc(-c2cc(O)nn2-c2ccccc2)c1
Reaction time: 2 h

Procedure:
60 ml of toluene and 10 g (0.12 mol) of manganese dioxide were added to 6.3 g (0.013 mol) of 4,5-dihydroxy-5-(3-hexadecyloxyphenyl)-3-hydroxy-1-phenylpyrazole and, heated and stirred for 2 hours on a steam bath. After inorganic substances were filtrated out, the remaining filtrate was concentrated and dried to a solid, and the solid product was crystallized in 20 ml of ethyl acetate. The product crystallized had a melting point of from 108° to 109° C. Yield: 5.8 g, 92.5%.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Br[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44]([C:46]2[CH:51]=[CH:50][C:49]([CH:52]([OH:54])[CH3:53])=[CH:48][CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: CC(O)c1ccc(C(=O)CBr)cc1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: CC(O)c1ccc(C(=O)Cn2ncc(OCc3ccccc3)cc2=O)cc1

Procedure:
5-Benzyloxy-2-{2-[4-(1-hydroxy-ethyl)-phenyl]-2-oxo-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (DMSO as solvent) from 624 mg (3.09 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 750 mg (3.09 mmol) 2-bromo-1-[4-(1-hydroxy-ethyl)phenyl]-ethanone (preparation 30a).
Reaction SMILES: C(OC(C1C=CSC=1N)=O)C.COC1C=C(OC)C=CC=1C[O:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[NH:20][C:19]1=[O:28]>>[OH:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[NH:20][C:19]1=[O:28]
Reactant: COc1ccc(COn2c(=O)[nH]c3sccc3c2=O)c(OC)c1
Agent: CCOC(=O)c1ccsc1N
Product: O=c1[nH]c2sccc2c(=O)n1O

Procedure:
2-Amino-thiophene-3-carboxylic acid ethyl ester was transformed to the O-protected intermediate 3-(2,4-Dimethoxy-benzyloxy)-1H-thieno[2,3-d]pyrimidine-2,4-dione using general procedure A1. Deprotection of this intermediate using general procedure D1 gave the title compound which was purified by mass triggered preparative HPLC. 1H NMR (DMSO-d6) δ 10.39 (bs, 1H), 7.16 (d, 1H, J=5.7 Hz), 7.12 (d, 1H, J=5.7 Hz); Electrospray MS: 183 (M−H); retention time: 1.25 min.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+].[ClH:20]>>[ClH:20].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)(C)N1CC(O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1ccc(O)cc1
Temperature: 140 °C
Yield: 58 %

Procedure:
A mixture of 11 parts of hydroquinone, 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved into 50 parts of 4 N-hydrochloric acid aqueous solution. The resulting solution was washed with 50 parts of chloroform. The water layer was acidified with concentrated hydrochloric acid, evaporated and solidified. The residue was dissolved in isopropyl alcohol and filtered. The filtrate was decolored with active carbon and allowed to cool. As a result, 6.9 parts of 1-(p-hydroxyphenoxy)-3-(tert.-butylamino)-2-propanol hydrochloride melting at 201°-203° C. were obtained. The yield was 58%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the resulting hydrochloride are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][N:1]6[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]6)=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NC(=O)C1CCNCC1
Product: NC(=O)C1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared from piperidine-4-carboxylic acid amide and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 198-205° C.; LC-MS: 483 (MH+); HPLC RT: 3.56 minutes.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:12]1(=[O:17])[N:11]([O:8][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])[C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: O=C1CCC(=O)N1O
Reactant: C#CCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: C#CCCCCC(=O)ON1C(=O)CCC1=O
Yield: 73.7 %

Procedure:
6-heptynoic acid (5) (≧97%, TCI, Portland, Oreg.) (1 g, 7.9 mmol, 1 equiv.) was dissolved in 100 ml of anhydrous methylene chloride. N-hydroxysuccinimide (NHS) (98+%, Acros, New Jersey) (2.3 g, 19.8 mmol, 2.5 equiv.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (98+%, Alfa Aesar) (2.3 g, 11.9 mmol, 1.5 equiv.) was added to the above solution. The resulting reaction mixture was stirred at room temperature overnight (18 hours) before 500 ml of a saturated sodium bicarbonate aqueous solution was added to it. The aqueous phase was extracted with 500 ml of ether. The ether extract was combined with the methylene chloride phase, washed with 500 ml of water and 500 ml of brine, and then dried with anhydrous magnesium sulfate. After magnesium sulfate was filtered away and the solvent was removed by rotary evaporation, an off-white solid (1.3 g, 72% yield) was obtained after being further dried overnight under vacuum. This solid was then used directly in the next step.
Reaction SMILES: COC[O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][C:10]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.[OH-].[K+]>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)(Cc1ccc(OCOC)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(O)cc1
Yield: 100.1 %

Procedure:
In a similar manner to that described in Reference example 2(b), a reaction was carried out using diethyl 2-(4-methoxymethoxybenzyl)-2-(2-phenoxyethyl)malonate (1.71 g) and potassium hydroxide and the reaction mixture was treated to afford the desired compound (1.25 g) as a syrup.
Reaction SMILES: [O:1]=O.[C:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:27]=[C:26]3[C:18]([C:19]4[CH:20]=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][C:24]=4[CH2:25]3)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[OH-].[K+].Cl>CC(=O)CC>[C:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:27]=[C:26]3[C:18]([C:19]4[C:24](=[CH:25]3)[C:23](=[O:1])[C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=4)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(OC(C)=O)cc3)ccc1-2
Reactant: O=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CCCCCOC1=CC=C2C(=Cc3cc(CCc4ccc(OC(C)=O)cc4)ccc32)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxygen was blown into a solution comprising 4-(2-(2-pentyloxyfluorene-7-yl)ethyl)phenyl acetate (4.2 g), powdery potassium hydroxide (1.0 g) and 2-butanone (80 mL) for one hour while refluxing by heating, and the solution was further stirred at a room temperature for one hour. A hydrochloric acid aqueous solution was added thereto, and then the product was extracted with chloroform to dry the chloroform layer on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off from this organic layer was purified by means of column chromatography (silica gel, eluting solvent: toluene) to obtain 4-(2-(2-pentyloxyfluorenone-7-yl)ethyl)phenyl acetate (2.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-(4-methylpiperazin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.24 (s, 3H), 2.41–2.47 (m, 4H), 2.63–2.69 (m, 2H), 3.46–3.53 (m, 8H), 3.69–3.72 (m, 4H), 7.0 (s, 1H) 7.04–7.12 (m, 2H), 7.19 (d, 1H), 7.25 (s, 1H), 7.57 (d, 1H), 7.88 (s, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 9.83 (s, 1H), 10.33 (s, 1H); Mass Spectrum: M+H+ 560.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:18])[CH3:21]
Reactant: N#Cc1ccn(-c2ccc(N)cc2F)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(-n2ccc(C#N)c2)c(F)c1
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
5-Amino-2-(3-cyano-1-pyrrolyl)fluorobenzene (4.6 g, 22.9 mmol) was stirred in dry pyridine (50 ml) 0°. Ethyl chloroformate (2.66 g, 24.5 mmol) was added, and stirring continued for 20 minutes at the same temperature before allowing the temperature to rise to ambient over 2 hours. Solvent was evaporated, the residue treated with iced water (50 ml), filtered off, and dried. Crystallisation of the crude product from ethanol (200 ml) gave the title product (4.9 g) mp 188-190°.