Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26](O)[CH3:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[Na+].[I-]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[CH2:27])[C:20]=4[O:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)oc4c(C(C)O)cccc34)c(C)nc12
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cccc2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
1-{3-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-benzofuran-7-yl}-ethanol (0.64 g, 1.63 mmol) is dissolved in CH2Cl2 (20 mL), treated with Et3N (0.27 mL, 1.95 mmol) and MsCl (0.14 mL, 1.79 mmol). The reaction is stirred at rt overnight. It is diluted with CH2Cl2 (40 mL), washed with H2O (2×40 mL); dried with Na2SO4; filtered and concentrated. The resulting crude material is dissolved in acetone (20 mL), refluxed with NaI (0.31 g, 2.04 mmol) overnight. The organic solvent is removed in vacuo, the residue is taken up with H2O (30 mL) and extracted with EtOAc (2×30 mL); the combined organic layers are dried with Na2SO4; filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.28 g, 0.75 mmol, 46%). 1H NMR (CDCl3): δ. 0.90 (t, J=7.0 Hz, 3H), 0.91 (t, J=7.0 Hz, 3H), 1.76-1.95 (m, 4H), 2.45 (s, 3H), 2.46 (s, 3H), 2.47 (s, 3H), 3.32-3.44 (m, 1H), 5.52 (dd, J=11.5, 1.3 Hz, 1H), 6.23 (dd, J=19.0, 1.3 Hz, 1H), 6.68 (s, 1H), 7.04 (dd, J=19.0, 11.5 Hz, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.16 (s, 1H), 7.29 (t, J=4.8 Hz, 1H) ppm. ES-MS (m/z): calcd for C24H27N3O (M+H)+: 374.5. found: 374.2.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10](O)=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[C:9]([S:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:8])=[O:7])=[CH:14][N:13]=[C:12]([S:15][CH3:16])[N:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
N-(1,1-Dimethylethyl)-4-hydroxy-2-(methylthio)-5-pyrimidinesulfonamide (5.0 g, 18.05 mmol) and finely ground PCl5 (3.95 g, 18.95 mmol, 1.05 eq) were mixed as dry solids. Enough POCl3 was added to make a slurry (7 mL) and the mixture was warmed. The mixture loosened, turned more yellow, evolved a gas, and became homogeneous over a 10 minute period. The reaction was cooled to ambient temperature, diluted with methylene chloride and toluene and evaporated to dryness in vacuo to yield a pale yellow solid. The crude solid was crystallized from ethanol and water to give 3.8 g (12.86 mmoles, 71%) of pure product, m.p. 117°-118° C. as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C2C=NN=N2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2C=NN=N2)cc1C(=O)O
Reaction time: 8 h

Procedure:
Combine methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate (56 mmol) and methanol (200 mL) and water (50 mL). Add 1 M aqueous solution of sodium hydroxide (62.5 mL, 62.5 mmol). Heat to reflux. After 8 hour, concentrate in vacuo to remove most of the solvent. Adjust the pH to about 1 to 2 using a 1 M aqueous hydrochloric acid solution, extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methoxy-5-(4H-triazol-4-yl)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.[N:16]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[CH:1]=[N:16]1
Reactant: O=N[O-]
Reactant: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2cn[nH]c2c1
Yield: 102 %

Procedure:
Ethyl 4-methyl-3-nitrobenzoate (105 g) was dissolved in glacial acetic acid (4 1), followed by stirring. To the solution, a solution of sodium nitrite (32 g) in water (80 ml) was added at once at a temperature of 10° C. to 15° C., and the resultant mixture was stirred at room temperature for 3 days. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to remove acetic acid. Water was added to the residue, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and dried. The obtained crystals was further washed with methanol and diethyl ether, and dried to give ethyl indazol-6-yl carboxylate (90 g), m.p. 125°-126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[CH:12]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:5]([CH:6]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:29](=[O:30])[N:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][CH3:18])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: CSc1cccc(Nc2nc(C)ccc2C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CSc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3ccc(C)nc32)c1

Procedure:
The procedure of Example 1 was repeated using 6-methyl-2-(3-methylthiophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 2), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-methylthiophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 158 to 159° C./AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [NH2:1]C1C=CC(CC2C=C(CC3C=CC(N)=CC=3)C=CC=2N)=CC=1.[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>O>[C:24]1(=[O:29])[NH:1][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Cc2ccc(N)c(Cc3ccc(N)cc3)c2)cc1
Solvent: O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A phthalimide-amine was prepared by mixing in a 2 liter glass resin kettle equipped with a mechanical stirrer, a heating mantle, a thermocouple connected to a temperature recorder, and an overhead water trap with a vertical condenser, 2.0 moles (600 grams) of BABA (a product of the E. I. duPont de Nemours & Company containing primarily 2,4-Bis(p-aminobenzyl)aniline) and 3.0 moles (444 grams) of phthalic anhydride. Heat was applied, and at about 100° C., the BABA melted and phthalic anhydride started slowly to react. The temperature was slowly allowed to rise to 150° C., at which time water began to condense overhead. Heating continued until 3.0 moles (54 grams) of water were collected. Since 2.0 moles of BABA contain 6 primary amines and three of them reacted with phthalic anhydride to form phthalimide linkages, 3 primary amine groups remained per 2 moles of BABA phthalimide. Since the molecular weight of this BABA phthalimide is 300+222-27=495, and contains 3 aminic hydrogens, its amine equivalent is 495/3=165, which corresponds to one epoxide equivalent or 180 grams of EPON-828 or 826 (the diglycidel ether of bisphenol-A such as is produced by the Shell Corporation). In other words, 47 grams of the aromatic amine of this example correspond to 51.3 grams of EPON-828.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH2:17]O)[CH:3]=1.C1C=CC(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:33][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CO
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate (10 g, 36.8 mmol) in anhydrous THF (100 ml) was added DPPA (8.3 ml, 38.6 mmol) and DBU (5.79 ml, 38.6 mmol). The mixture was stirred overnight and then was partitioned between ethyl acetate and water. The organic layer was washed with brine, and was concentrated in vacuo to a crude oil (14.6 g). Purification was accomplished by silica gel chromatography, eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%) to give tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:22])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH2:30])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)Nc3ccccc3N)c2)CC1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of 4-(3-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (5.80 g, 18.95 mmol) and 1,1-carbonyldiimidazole (CDI) (3.07 g, 18.95 mmol) in acetonitrile (120 mL) was stirred for 3 h at room temperature, then 1,2-phenylenediamine (2.25 g, 20.85 mmol) was added. The resulting suspension was refluxed for 3 h, then cooled to room temperature and the solvent removed under reduced pressure. The resulting residue was diluted with dichlomethane (200 mL), washed with water (3×40 mL) and the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was recrystallized from EtOAc to obtain 2.99 g (40%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Yield: 97.9 %

Procedure:
5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N2. The flask was placed in an oil bath at 100° C. and heated until the 5-chloro-2-nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2×) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50° C. to a constant weight to yield 670 g (97.8%) of the title compound as a yellow powder.
Reaction SMILES: [C:1]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Mg].[Mg].BrC1C2C(=CC=CC=2)C=CC=1.[CH2:25]([N:27]([CH2:41][CH3:42])[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[CH3:26]>O1CCCC1>[CH2:41]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][N:30]1[C:34]([OH:35])([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]1=[O:40])[CH3:42]
Reactant: CCN(CC)CCN1C(=O)c2ccccc2C1=O
Reactant: Brc1cccc2ccccc12
Agent: [Mg]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)c2ccccc2C1(O)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a tetrahydrofuran solution of magnesium 1-naphthylbromide prepared from 1.22 g of metallic magnesium and 10.35 g of α-bromonaphthalene in 50 ml of tetrahydrofuran was added a solution of 6.16 g of N-(2-diethylaminoethyl)-phthalimide in 10 ml of tetrahydrofuran under ice cooling. After stirring for 2 hours under ice cooling, the mixture was concentrated under reduced pressure. To the residue were added 6.61 g of ammonium sulfate, 100 ml of ethyl ether and 100 ml of water. After shaking, the aqueous layer was discarded and 100 ml of water was added to the organic layer. The pH was adjusted to 1.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 100 ml of ethyl ether was added to the aqueous layer. The pH was adjusted to 11.5 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded. After the organic layer was washed with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude crystals obtained were recrystallized from diisopropyl ether to give 2.85 g of 2-(2-diethylaminoethyl)-3-hydroxy-3-(1-naphthyl)isoindolin-1-one (Compound 20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.[CH2:22]1COC[CH2:23]1.CO.O[Li].O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[CH:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: C1CCOC1
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To 450 mg (1.36 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 9 mL of a solvent mixture of THF/MeOH (7:2) followed by 172 mgs of LiOH—H2O in 1 mL of H2O. The mixture was stirred for 30 min at rt. The mixture was concd, treated with 10 mL of water and acidified with conc. HCl (approx. 0.4 mL). The producted oiled out of solution and was extracted three times with diethyl ether. Combined extracts were dried and concd to afford 0.32 g of a crude yellow solid. Chromatography (C18, Gilson 10×4 cm, 7 injections of 50 mgs each) afforded 0.18 g (43.7%) of a white solid: 1H NMR (d6-acetone/400 MHz) 3.74 (s, 1H), 6.03 (q, 1H, 6.8 Hz), 7.61 (m, 2H), 7.92 (s, 1H); 13C NMR (d6-acetone/400 MHz) 72.0 (q, J=33.2 Hz), 80.0, 81.6, 118.3, 119.6, 121.7, 121.8 (q, J=0.7 Hz), 124.2 (q, J=286.6 Hz), 132.5, 136.1, 136.7, 149.9, 164.6; 19F NMR (d6-acetone/400 MHz) −79.6 (d, 3F, J=6.5 Hz); MS (ES+) 303 (M+1, 27), 291 (65), 289 (51), 235 (100), 233 (79); MS(ES−) 301 (M−1, 100), 303 (35); HRMS (EI−) m/z calcd for (C13H5O3ClF3) 300.9874, found 300.9837.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH:48][CH2:49][CH2:50][NH:51][CH2:52][CH2:53][OH:54]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:51]([CH2:52][CH2:53][OH:54])[CH2:50][CH2:49][OH:48])=[O:44])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: OCCNCCO
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCO)CCO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(2-hydroxy-ethylamino)-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3294.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][CH:7]=[CH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.ClCCl>O>[CH3:6][CH:7]=[CH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:27]
Reactant: CC=Cc1cc2ccccc2s1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC=Cc1sc2ccccc2c1C(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Tin tetrachloride (2.83 mL, 24.12 mmol) was added dropwise over a 10 minute period to a stirred solution of 2-all-3-yl-benzo[b]thiophene (3.51 g, 20.1 mmol), anisoyl chloride (3.61 g, 21.1 mmol) and dichloromethane (70 mL) under a dry nitrogen atmosphere. After 5 h., the mixture was warmed up and stirred at 0° C. for 1 h. The reaction mixture was added to water and extracted with ethyl ether. The ethyl ether extract was washed with sat. aq. sodium bicarbonate and brine. Silica gel (100 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 92:8 petroleum ether:ethyl acetate) to provide the title compound as an oil (4.42 g, 71 %): NMR (CDCl3); δ 7.88-7.76 (multiplet with overlapping doublet at 7.84, J=9 Hz, 3H), 7.50-7.44 (m, 1H), 7.34-7.24 (m, 2H), 6.94 (d, J=9 Hz, 2H), 6.00-5.85 (m, 1H), 5.20-5.13 (m, 2H), 3.90 (s, 3H), 3.62 (d, J=6 Hz, 2H); MS (EI): [M+] 308 (50%); Anal. Calc. for C19H16O2S: C, 74.00, H, 5.23, N, 0.00. Found: C, 73.16, H, 5.13, N, 0.09.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O)(=[O:15])C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:15])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC1(C)CCc2ccc(Br)cc21
Reactant: CC(=O)O
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of 6-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (3.6 g, 16 mmol) in acetic acid (50 mL) was added to a solution of CrO3 (9.6 g, 96.0 mmol) in 50% aqueous acetic acid (50 mL). This solution was heated for 3 h at 60° C. At completion, the reaction mixture was quenched by the addition of isopropanol (20 mL). The quenched reaction was partitioned between EtOAc (200 mL) and a 0.25 M aqueous NaOH (100 mL). The layers were separated and the organics were extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. After purification by flash chromatography over silica gel (50% EtOAc/hexanes eluent), 5-bromo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (2.91 g, 76% yield) was isolated as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (s, 1H), 7.47-7.58 (m, 2H), 2.58 (s, 2H), 1.42 (s, 6H); MS (EI) m/z=240.1 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:31])[NH:7][C:8]1[CH:30]=[CH:29][C:11]2[N:12]([CH:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:17]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]3[CH:9]=[C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:31])[CH:30]=[CH:29][C:11]2=3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)CCCCN2C1CCNC1)c1cccs1
Yield: 113.3 %

Procedure:
A solution of compound 4 (0.8 g, 1.815 mmol) in methanol (10 mL) was treated with 1 N HCl (10 mL) and the resulting mixture was refluxed for 30 minutes. The reaction was brought to room temperature and solvent was evaporated. The crude product was dissolved into water (10 mL), filtered and washed. Water was evaporated to obtain compound 48 (0.7 g, 93%) as a solid. 1H NMR (DMSO-d6) δ 11.44 (s, 1H), 9.78-9.65 (m, 3H), 8.78 (s, 1H), 8.17-8.15 (m, 2H), 7.37 (t, 1H, J=4.2 Hz), 7.20-7.08 (m, 3H), 3.50-3.40 (m, 1H), 3.38-3.26 (m, 1H), 3.17-2.90 (m, 4H), 2.76 (brt, 2H), 2.30-2.20 (m, 1H), 2.00-1.90 (m, 1H), 1.70-1.50 (m, 4H); ESI-MS (m/z, %): 341 (MH+, 38), 272 (100); ESI-HRMS calculated for C19H25N4S (MH+, free base), calculated: 341.1794; observed: 341.1801; HPLC-purity: 98.20% by area.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[SH:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.[OH-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>CO>[F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[S:21][CH2:28][CH:27]=[CH2:26])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1
Reactant: C=CCBr
Reactant: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.7 g of (11β,17β)-9-Fluoro-11-hydroxy-17-mercaptoandrosta-1,4-dien-3-one dissolved in 100 ml of methanol, there was added 1 g of sodium hydroxide followed by 2.5 ml of allyl bromide (nitrogen atmosphere). The alkylation was complete after 1 hour of stirring at room temperature. The solution was partly evaporated, water was added and the resulting solid filtered and washed with water. Crystallization of the solid from ethyl acetate-petroleum ether furnished 1.08 g of the analytical sample, melting point 173°-175° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].C[O:10][C:11]1[C:16]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[N:31][C:32]=4[NH2:34])[N:27]([C@H:35]4[CH2:40][CH2:39][C@H:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)[N:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][N:12]=1>Br.C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6].[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([C@H:35]3[CH2:40][CH2:39][C@H:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)[N:26]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:16]4[C:11](=[O:10])[NH:12][CH:13]=[CH:14][CH:15]=4)=[CH:24][CH:23]=3)[C:33]=12
Reactant: COc1ncccc1CNc1ccc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5ccc[nH]c5=O)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-3-(4-[(2-methoxy-3-pyridyl)methyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.105 g, 0.000199 mol) was dissolved in 30% hydrogen bromide in acetic acid (4 mL) and the mixture was refluxed for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)methyl]-1,2-dihydro-2-pyridinone diacetate (0.0204 g, 0.0000324 mol) as a white solid.