Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1C(OC(C)(C)C)=O>CO>[ClH:1].[ClH:1].[F:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(C2CCCN2)c(F)c1)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of 4 N hydrochloric acid-dioxane solution was added to a methanol (50 ml) solution of 4.4 g of t-butyl 2-(2-fluoro-4-((pyrazin-2-ylcarbonyl)amino)phenyl)pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 1 hour. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(O)C>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CNCc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Methyl 4-(Aminomethyl)benzoate (6.88 g, 34.2 mmol) and 4-hydroxybenzaldehyde (4.60 g, 37.7 mmol) were dissolved in ethanol (300 mL), the mixture was heated to reflux for 6 hours, sodium borohydride (2.07 g, 54.7 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane. The resulting organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was reprecipitated with dichloromethane-hexane to give the title compound (4.90 g; yield, 52%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:10]2[C@H:4]([C:5](=[O:17])[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[Si:23]([O:1][C@H:2]1[CH2:11][N:10]2[C@H:4]([C:5](=[O:17])[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]2=[O:12])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=C1Nc2ccccc2C(=O)N2C[C@H](O)C[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2C(=O)Nc3ccccc3C(=O)N2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
To a suspension of (2R,11aS)-2-hydroxy-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c][1,4]benzodiazepin-5,11-dione (50 g) prepared in Reference Example 21 and imidazole (33.7 g) in N,N-dimethylformamide (500 ml), there was added 37.9 g of tert-butyldimethylsilyl chloride at room temperature in a nitrogen gas atmosphere and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into one liter of ice water and the crystals precipitated were recovered by filtration. The crystals were washed with water and then dried to give 72.5 g (yield 99.9%) of (2R,11aS)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([OH:21])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[C:19]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:21]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 0.54 g, 2.8 mmol) and 3-bromo-5-trifluoromethyl benzoic acid (0.81 g, 3.0 mmol) in DMF (7 mL) was added TBTU (0.96 g, 3.0 mmol) and DIPEA (1.41 g, 10.9 mmol). The reaction mixture was stirred under nitrogen overnight at RT and then partitioned between ethyl acetate and an aqueous NaHCO3 solution. The aqueous phase was extracted trice with ethyl acetate. The combined organic solutions were washed trice with water and then dried by a phase separator column. The solvent was removed by to evaporation and the product was purified by chromatography on silica gel (ethyl acetate-heptane 10% to 17%). There was obtained 0.86 g (68%) of 3-bromo-N-[(25)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide. 1H NMR (500 MHz, CDCl3): 2.1-3.8 (cm, 8H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.8-7.4 (cm, 6H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:20])[CH:13]=[C:14]([OH:19])[C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:19][C:14]1[C:15]2[C@@H:16]3[C@@H:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5]4)[CH2:8][CH2:9][C:10]=2[CH:11]=[C:12]([O:20][CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CC[C@@H]2O
Reactant: CCCCBr
Product: CCCCOc1cc2c(c(OCCCC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]1CC2

Procedure:
Analogously to Example 12, 500 mg. of 8α -estra-1,3,5(10)-triene-1,3,17β-triol is reacted with 1.5 ml. of n-butyl bromide and worked up. Yield: 230 mg.
Reaction SMILES: C([NH:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]1[CH:19]([CH3:20])[CH2:18][CH:17](C)[C:16]1([CH3:23])[CH3:22])(OCC1C=CC=CC=1)=O.[CH3:25]O>[Pd]>[NH2:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]1[C:16]([CH3:22])([CH3:23])[CH2:17][CH2:18][C:19]1([CH3:20])[CH3:25]
Reactant: CC(COC1C(C)CC(C)C1(C)C)NC(=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: CC(N)COC1C(C)(C)CCC1(C)C

Procedure:
N-Cbz-1-(2-Aminopropoxy)-2,2,3,5-tetramethylcyclopentane is dissolved in CH3OH and hydrogenated over 5% Pd/C in a Parr hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 1-(2-amino-propoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])O.[Na+].Cl>O.CCOCC>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 45.3 %

Procedure:
4-Amino-3-methylbenzoic acid (5.0 g) was suspended in water (80 ml) and, thereafter, an ether solution (20 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (3.6 g) were alternately added to the suspension under cooling with ice. Following stirring for 2.5 h at room temperature, an ether solution (95 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (7.2 g) were further added alternately under cooling with ice, and the mixture was stirred for 1.5 h at room temperature. After rendering the reaction solution acidic with 4N HCl, the separating insoluble matter was recovered by filtration. The recovered solids were vacuum-dried to yield the end product (2.8 g).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[C:9](=[CH:13]OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: CC(=N)NC(C)C
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 10.9 g (yield: 61%) of 5-acetyl-1-iso-propyl-2-methylimidazole as pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][CH3:14])[CH:9]=2)[CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13]([Br:15])[CH3:14])[CH:9]=2)[CH:4]=1
Reactant: CCc1ccc2cc(OC)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2cc(C(C)Br)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 1.0 gram of 2-methoxy-6-ethylnaphthalene and 1.05 grams of N-bromosuccinimide in 10.0 ml. of carbon tetrachloride was refluxed for 1 hour. During this time, the solids migrated from the bottom of the reaction flask to the top. The mixture was cooled to room temperature and the solids were separated from the liquid by filtration on a small suction filter funnel. The carbon tetrachloride solvent was removed using a rotary vacuum evaporator. The yield was 1.55 grams of a pale oil that solidified at room temperature. Based on 1H nuclear magnetic resonance data, the product had a structure consistent with that of 2-methoxy-6- (1-bromoethyl) naphthalene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:47]1[C:52](=[O:53])[CH2:51][CH2:50][C:48]1=[O:49])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][N:47]2[C:52](=[O:53])[CH2:51][CH2:50][C:48]2=[O:49])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of 5-(9-Carboxy-nonyloxy)-isophthalic acid di-tert-butyl ester (156 mg, 0.34 mmol) in dry THF (2 ml) was added TSTU (125 mg) and DIPEA (0.08 ml). The mixture was stirred under nitrogen over night. The mixture was concentrated. The residue was redissolved in EtOAc and filtered. The filtrate was washed with 0.1N HCl (2×), and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1.C(O)C.O.[OH-].[Li+]>O>[CH3:1][O:2][C:3]1[C:8]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: COC(=O)C(C)c1cncnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ncncc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.21 g (1.06 mmol) of methyl 2-(4-methoxypyrimidin-5-yl)propanoate from Step B above in 0.5 mL of water and 1.5 mL of ethanol was added 81 mg (1.9 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 3 mL of 2.0 N aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound as an off white solid (70 mg, 36%). 1H-NMR (500 MHz, CD3OD) δ: 8.67 (s 1H), 8.4 (s, 1H), 4.07 (s, 3H), 3.9 (q, J=7 Hz, 2H), 1.58 (d, J=7 Hz, 3H). LC-MS: m/z (E/S) 183 (MH)+.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:39]=[CH:38][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:16][N:17]([C:19]([C:21]4[CH:39]=[CH:38][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:18]3)[CH2:13][CH2:14]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 434 (87.7 mg, 0.164 mmol) in CH2Cl2 (1 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to give compound 33a, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To a solution of 3,5-difluoro-4′-acetoxystilbene (0.69 g, 2.5 mmol) in MeOH (10 ml) was added 5 mL 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3,5-difluoro-4′-hydroxystilbene (0.51 g, 88%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.40 (m, 2H), 7.05-6.83 (m, 6H), 6.67 (tt, 1H), 4.88 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 164.49 (d), 162.47, 156.01, 141.29, 130.90, 128.53, 124.74, 115.96, 109.03 (t), 102.53 (t); 19F NMR (CDCl3, 282 MHz) δ −31278.95 (t, J=1720.2 Hz); HRMS (EI+) found 232.0715 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Product: COc1cc(C(=O)CC(Cc2ccc(NC(=O)c3ccccc3)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Yield: 53.4 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol) with benzoyl chloride (0.039 mL, 0.34 mmol) provided 67 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-benzoyl)aminophenyl)ethylamide as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CC=Cc2c(Cc3ccc(-c4cnn(C)c4)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.092 mmol) in 2 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.18 mL, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.057 g, 0.28 mmol), and bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 0.0078 mmol). The reaction was heated at 100° C. for 16 h, cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 483.1 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.95 (br s, 2H), 7.61-7.39 (m, 3H), 4.78 (s, 2H), 4.49 (s, 2H), 4.23 (br s, 1H), 3.92 (s, 3H), 3.74 (br s, 1H), 3.20 (s, 3H), 2.11 (br s, 1H), 1.83-1.63 (m, 5H), 1.29-1.23 (m, 2H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([Se:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=2)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.C(O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([Se:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:15][C:16]2[C:17]([CH3:25])([CH3:26])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cc3)c(OCCCCCCCC(=O)O)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 410 mg (0.7 mmol) of ethyl 4-[3-(7-methoxycarbonylheptyloxy)-5,5,8,8-tetramethyl5,6,7,8-tetrahydro-2-naphthylselanyl]benzoate with 280 mg (7 mmol) of sodium hydroxide in a THF/ethanol mixture (5 ml/5 ml), 326 mg (85%) of a white powder are obtained. m.p.: 183° C.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:12]([C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:37](Cl)=[O:38])[N:27]=[C:28]3[CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:37]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:11])=[O:38])[N:27]=[C:28]3[CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Cl)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)c1ccccc1N
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Nc4ccccc4C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 57.4 %

Procedure:
The title compound (30 mg) was prepared following the same procedures that was described for example 432 from methyl-2-aminobenzoate (0.1 mmol, 15.1 mg) and 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl chloride (46 mg, 0.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(Nc3ccccc3)nc2n1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine (1.0 eq) and aniline (1.0 eq) were heated in toluene at 60° C. for 15 h. Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give intermediate 5-chloro-7-morpholino-N-phenylthiazolo[4,5-d]pyrimidin-2-amine which was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.0 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.10 eq) in 1M KOAc aqueous solution (3.0 eq) and a 4× volume of acetonitrile and heated to 150° C. in a sealed microwave reactor for 10 min. Upon completion, reaction mixture was concentrated in vacuo and crude mixture was purified by silica gel chromatography to give 146. MS (Q1) 406 (M)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]([Cu])#[N:14].Cl>CN(C=O)C>[C:13]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1O
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (a) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature was allowed to decrease to 80° C. and HCl (500 mL) and FeCl3 (165.0 g) were added. The reaction mixture was stirred for 30 min., concentrated and partitioned between H2O and DCM. The organic layer was dried, concentrated the residue recrystallized from methylethyl ketone giving the sub-title compound in a 61% yield.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7]([C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[CH:14]=O)=O)C.S(=O)(=O)(O)O.O>C(O)C>[CH3:1][N:2]1[C:7](=[O:6])[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[CH:14]=[N:3]1
Reactant: CCOC(=O)c1cc[nH]c1C=O
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cn1ncc2[nH]ccc2c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of methylhydrazine (4.84 g) and 3-ethoxycarbonyl-2-formylpyrrole (3.34 g) in ethanol (30 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was further refluxed for 19 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=19:1) to provide the title compound as white powder (1.81 g; yield 61%). 1 H-NMR (DMSO-d6) δ: 3.68(3H,s), 6.65(1H,d,J=2.8Hz), 7.42(1H,t,J=2.8Hz), 8.17(1H,s), 12.02(1H,m).