Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5](=[N:9][C:10]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)[O:6][CH2:7][CH3:8])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:7]([O:6][C:5]1[CH2:4][N:1]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:10]=2[N:9]=1)[CH3:8]
Reactant: CCOC(CN=[N+]=[N-])=Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reaction time: 1.5 h

Procedure:
To a solution of 2.5 parts of 2-(2-azido-1-ethoxyethylideneamino)-5-nitrobenzophenone produced in Step (2) in 30 parts by volume of benzene is added with stirring 1.78 parts of triphenylphosphine. The mixture is stirred for further 1.5 hours and the solvent is removed by distillation. The residue is extracted with a mixture of n-hexane and acetone (7:3), and the soluble fraction is purified by means of chromatography employing Silica Gel, whereupon 2-ethoxy-7-nitro-5-phenyl-3H-1,4-benzodiazepine is obtained as pale yellow crystals. Recrystallization from ether-n-hexane gives pale yellow prisms melting at 143°-145° C.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:5]=1)[CH:2]=[CH2:3].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([C:4]1[C:9]([O:10][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([C:13]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)=[O:14])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1O
Reactant: CCOC(=O)CBr
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)OCC
Yield: 99.8 %

Procedure:
1.13 g of 6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenol and 0.67 g of ethyl bromoacetate are treated in the same manner as described in Example 1 to give 1.44 g of ethyl [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetate. IRνmaxliquid (cm-1): 1755, 1735, 1665, 1640, 1585, 1550.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].O1CCOCC1>C(OCC)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:12][CH2:13][C:14]#[CH:15])[CH3:17]
Reactant: CCNCC
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: C#CCCN(CC)CC
Temperature: 80 °C
Yield: 64.2 %

Procedure:
Prepared using methodology described by Olomucki, M., et al. Ann. Chim. 1960, 5, 845. A stirred mixture of but-3-ynyl 4-methylbenzenesulfonate (21.2 g, 94.5 mmol), diethylamine (6.91 g, 94.5 mmol), and p-dioxane (100 mL) was heated to 80° C. under N2 for 6 hours. After cooling to room temperature, the suspension was diluted with diethyl ether (100 mL) and filtered. The solids were washed with diethyl ether (50 mL). The filtrate was concentrated to a brown oil. The crude was co-distilled (55-65° C.) with p-dioxane under a mild vacuum (10-50 torr). The product was obtained as an oil (7.6 g, 27%), in a 42:58 mixture with p-dioxane based on 1H NMR. 1H NMR (400 MHz, CDCl3) δ 2.70 (t, J=8 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 2.32 (m, 2H), 1.97 (t, J=3 Hz, 1H), 1.04 (t, J=7 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:16][CH:15]([CH2:17]O)[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].CCN(CC)CC.S(Cl)(C)(=O)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[C:42]([CH:47]2[CH:52]([CH3:53])[CH2:51][CH2:50][CH:49]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[NH:48]2)=[N:43][CH:44]=[CH:45][CH:46]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:40][C:41]1[C:42]([CH:47]2[CH:52]([CH3:53])[CH2:51][CH2:50][CH:49]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[N:48]2[CH2:17][CH:15]2[CH2:16][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:14]2)=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1cccnc1C1NC(c2ccccn2)CCC1C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC(CO)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: Cc1cccnc1C1C(C)CCC(c2ccccn2)N1CC1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a 0° C. solution of [1-(2-nitro-benzenesulfonyl)-azetidin-3-yl]-methanol (165 mg, 0.606 mmol) in EtOAc (15 mL) was added Et3N (0.101 mL, 0.727 mmol) then mesyl chloride (0.052 mL, 0.666 mmol). The reaction mixture was stirred for 1 hour at room temperature. The precipitate was filtered through a plug of Celite and was washed with EtOAc. The filtrate was concentrated and the crude mesylate was dissolved in DMF (5 mL). To this solution was added DIPEA (0.211 mL, 1.20 mmol) and 3,3′-dimethyl-1′,2′,3′4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (162 mg, 0.606 mmol) and the mixture was heated at 80° C. for 17 hours. Saturated NaHCO3 (15 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by radial chromatography on silica gel (Et2O saturated with NH4OH) to give 3,3′-dimethyl-1′-[1-(2-nitro-benzenesulfonyl)-azetidin-3-ylmethyl]-1′,2′,3′4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (168 mg, 53%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[O:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1.C(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]1[CH2:21][CH:22]=[C:23]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(C3=CCOCC3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol), Pd(dppf)Cl2.DCM (408 mg, 0.5 mmol) and sat. NaHCO3 solution (2 mL). The mixture was stirred at 100° C. for 2 h under nitrogen. The mixture was cooled to rt and diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 930 mg (86%) of the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96 (2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s), 7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz). [M+H] Calc'd for C15H16O2, 229. Found, 229.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.C[NH:17][C:18](=[NH:20])S.[OH-].[Na+]>O>[C:18]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[NH:17])[NH2:20]
Reactant: NNC(=O)c1ccccc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N=C(N)NNC(=O)c1ccccc1
Yield: 61.4 %

Procedure:
A solution of benzoic acid hydrazide (10.3 g), methylisothiourea sulfate (21.0 g), sodium hydroxide (3.12 g) and water (150 ml) was stirred for 99 hours at room temperature. The resulting solid was collected by filtration and washed with water to give 8.28 g of a white solid (yield 61%).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O>CCOCC>[CH2:17]([O:16][C:14]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:15])[CH3:18]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl alcohol (2.70g.; 0.025 mole) was added to a solution of ethyl 4-hydroxybenzoate (4.15g.; 0.025 mole) in dry ether followed by the careful addition of phosphorus pentachloride (2.5g). The mixture was boiled under reflux for 24 hrs. then poured into water and the ether layer removed. The aqueous solution was extracted with ether and the combined organic extracts dried (anhyd. MgSO4) to yield, on evaporation and purification by chromatography, 4-ethoxycarbonylphenoxy phenyl methane, m.p. 45°C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH:17](O)[CH3:18]>O1CCCC1>[CH3:18][C:17]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[NH:15][CH:16]=1
Reactant: CC(O)CN
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (5.0 g), 3-aminopropan-2-ol (2.6 g), molecular sieves 4A (30 g) and tetrahydrofuran (70 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (130 ml). To the solution were added 2-bromomesitylene (5.3 g), tetrakistriphenylphosphine palladium (0.77 g) and potassium carbonate (7.3 g), and the mixture was stirred at 150° C. for 4 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[N:40][C:41]#[N:42])OC5C=CC=CC=5)[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:45]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[NH:45])[NH:40][C:41]#[N:42])[CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Agent: [OH-]
Solvent: CC(C)O
Product: N#CNC(=N)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Phenyl 4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6] cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-N-cyano-1-piperidinecarboximidate (2.62 g) (Formula 2.0, prepared as described in Example 1 above) was dissolved in 2-propanol (50 ml) and concentrated ammonium hydroxide (4 ml) was added. The mixture was stirred at 25° C. for 24 h and then evaporated to dryness. The residue was triturated with diethyl ether (2×250 ml) and the ether was discarded. The remaining product was chromatographed on a silica gel column (60×2.5 cm) using 4% (10% concentrated ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (Formula 3.0) (1.967 g;85%), FABMS: m/z 584.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[F:21].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:17]=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[C:13]=2[F:12])=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: COc1cccc(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 111.5 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoyl chloride 21d (3.4 g, 13.4 mmol) and 1,2-difluoro-3-methoxybenzene 21b (2.4 g, 16.7 mmol) in dichloromethane (40 mL) was added anhydrous aluminium chloride (1.82 g, 13 mmol) at 0° C. The mixture was stirred at 0° C. for 16 hours. Then the reaction mixture was quenched with hydrochloric acid (4 mL, 2 M) and warmed up to room temperature. The mixture was extracted with dichloromethane (40 mL×4). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21e as yellow liquid (5.4 g, 96.4%). This material was not further purified.
Reaction SMILES: C[O-].[Na+].[NH2:4]/[C:5](/[C:12]([F:15])([F:14])[F:13])=[CH:6]\[C:7](OCC)=[O:8].[CH3:16][N:17]=[C:18]=[O:19].O>CS(C)=O>[CH3:16][N:17]1[C:7](=[O:8])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:18]1=[O:19]
Reactant: CN=C=O
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)cc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a pre-mixed solution of sodium methoxide (55 mmol, 2.97 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (55 mmol, 10.0 g) in DMSO (19 mL, dried over molecular sieves) was added methyl isocyanate (55 mmol, 3.2 g) in DMSO (2.5 mL) over 15 min at 20° C. The solution was stirred for 15 min and then another portion of sodium methoxide (27.5 mmol, 1.34 g) was added. After stirring for 15 min at 20° C., methyl isocyanate (14 mmol, 0.8 g) was added at this temperature. After a further 15 min, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting yellow suspension was poured into water (50 mL) to obtain a light yellow solution. The neutral impurities were extracted into diethyl ether (3×50 mL). The aqueous layer was acidified with concentrated hydrochloric acid to afford a white solid. The solids were collected by filtration and were washed with water. After air drying, 6.79 g (63% yield) of 3-methyl-6-(trifluoromethyl)uracil was obtained as a white solid: mp 235-237° C. EI-HRMS m/e calcd for C6H5F3N2O2 (M+) 194.0303, found 194.0303.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)(=[O:23])=[O:22])([O-:14])=[O:13].[CH2:33]([N:35]1[C:41](=[O:42])[C:40]([CH3:44])([CH3:43])[C:39](=[O:45])[N:38]([CH3:46])[C:37]2[CH:47]=[C:48]([O:51][CH2:52][CH2:53][CH2:54]I)[CH:49]=[CH:50][C:36]1=2)[CH3:34]>C(OCC)(=O)C.O>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]([CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:54][CH2:53][CH2:52][O:51][C:48]1[CH:49]=[CH:50][C:36]2[N:35]([CH2:33][CH3:34])[C:41](=[O:42])[C:40]([CH3:44])([CH3:43])[C:39](=[O:45])[N:38]([CH3:46])[C:37]=2[CH:47]=1)(=[O:22])=[O:23])([O-:14])=[O:13]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Potassium carbonate (1.89 g, 13.7 mmol) was added to a DMF solution (50 ml) of 2-nitro-N-(2-pyridin-3-ylethyl)benzene sulfonamide (1.40 g, 4.56 mmol) and 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.16 g, 5.0 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to thereby obtain 2.99 g (yield: quantitative) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Cl)[N:7]=1.[CH3:14][O-:15].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:15][CH3:14])[N:7]=1
Reactant: C[O-]
Reactant: CN(C)CCNc1cccc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(NCCN(C)C)n1
Yield: 80.9 %

Procedure:
A solution of 2-(2-dimethylaminoethylamino)-6-chloropyridine (10.0 g, 0.05 mole) in dimethylformamide (50 ml) containing sodium methoxide (3.5 gm, 0.065 mole) is heated at 110°-120° for two hours. The solution is cooled and the sodium chloride filtered. After removing the solvent in vacuo, the residue is dissolved in dilute hydrochloric acid (10%), washed with methylene chloride, made alkaline with sodium carbonate and the product is extracted into methylene chloride. After drying this solution over anhydrous sodium sulfate and filtering through charcoal, the solvent is removed under vacuum to give the oily product (7.9 g). This is used without further purification in the succeeding step.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ccccn1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 31.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-urea (140 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:26])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]=[N:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:25][C:19]1([CH3:24])[C:20]([CH3:22])([CH3:23])[O:21][B:17]([C:15]2[CH:14]=[N:13][N:12]([CH2:11][CH2:10][C@H:9]([OH:8])[CH3:26])[CH:16]=2)[O:18]1
Reactant: C[C@H](CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
A solution of (R)-1-(3-[(tert-butyldimethylsilyl)oxy]butyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 69C, 5 g, 13.1 mmol) in THF (20 mL) was treated with tetrabutylammonium fluoride (26 mL, 1M in THF) and stirred for 24 hrs at RT under nitrogen atmosphere. Tetrahydrofuran was evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, 1% methanol in dichloromethane) to give colorless gum (600 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.64 (s, 1H), 4.15-4.23 (m, 2H), 3.60-3.3.71 (m, 1H), 1.7-1.98 (m, 2H), 1.23 (s, 12H), 1.12 (s, d, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]([NH2:44])=[O:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]([NH2:44])=[O:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1(C)OB(c2cnn(CCC(N)=O)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CCC(N)=O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanamide (7.6 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10) to afford the desired product (3.2 mg). LCMS (M+H)+: m/z=476.2.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[NH:20]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][S:30][CH2:31][CH2:32]N)[N:28]=1)[C:21]([NH2:23])=[NH:22]>N1C=CC=CC=1>[NH:20]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][S:30][CH2:31][CH2:32][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:7][N:6]=2)[N:28]=1)[C:21]([NH2:23])=[NH:22]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
2-Nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (5.21 g) and 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (2.98 g) were heated under reflux in dry pyridine for 9 hours. The mixture was evaporated and the residue was washed with water to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which was treated with hydrogen chloride in ethanol-ether to give the trihydrochloride (0.92 g). This was converted into the free base by dissolving the material in water, adjusting the mixture to pH 9 with sodium bicarbonate, and extracting the mixture with chloroform and evaporating the extracts to dryness. A sample of the free base recrystallised from aqueous 2-propanol had m.p. 161°-164°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[CH:7][NH2:8])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]([O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1NOC(=O)C(F)(F)F)[CH2:17][CH3:18]>C(O)C>[CH3:1][C:2]1[C:6](=[CH:7][NH:8][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCCOc1ccccc1NOC(=O)C(F)(F)F
Reactant: CC1=NN(c2ccccc2)C(=O)C1=CN
Solvent: CCO
Product: CCCOc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
3-methyl-4arninomethylene-1-phenyl-4,5-dihydro-pyrazol-5-one (2 g) and 2-propoxyanilino-trifluoroacetic acid salt (1.6 g) are refluxed 1.5 hours in ethanol.