Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][N:26]([CH3:31])[C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Cc2ccc(CN3CCNC3=O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cc2ccc(CN3CCN(C)C3=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was added P-374 (21 mg, 0.05 mmol), THF (1 mL) and the solution was cooled to 0° C. Sodium hydride (3 mg, 0.076 mmol) was added and after 15 minutes at room temperature, methyl iodide (6 uL, 0.101 mmoL) was added. The reaction was stirred for 30 minutes at room temperature and then 1 mL of water was added. The THF was evaporated and the product was extracted with ethyl acetate and concentrated. The residue was passed through a silica gel plug eluting with methanol, which afforded P-375 (18.1 mg, 82%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=1.6 Hz, 1H), 7.60 (dd, J=2.0, 7.9 Hz, 1H), 7.50-7.39 (m, 2H), 7.37 (s, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.31 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 3.24 (s, 4H), 2.67 (s, 3H) ppm. LC/MS=97.8%, 440.1 (APCI+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH3:17])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)c1ccc(C(C)Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)n2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.20 g, 1.0 mmol), methyl 4-(1-chloroethyl)benzoate (0.2 g, 1.0 mmol), potassium carbonate (0.28 g, 2.0 mmol), and 18-crown-6 (3 mg) in DMF (5 mL) was stirred at 80° C. for 8 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford methyl 4-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}benzoate, which was used in next step without purification. MS ESI calc'd. for C19H26BN2O4 [M+H]+ 357. found 357.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of benzylamine (0.77 mL, 7.0 mmol), ethyl 3-fluoro-4-nitrobenzoate (1.0 g, 4.7 mmol) and TEA (2 mL) was heated in DMF (10 mL) for 18 hr at 70° C. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then 1N HCl (2×100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.52 g (˜100%) of crude ethyl 3-(benzylamino)-4-nitrobenzoate as an orange solid. This material was used without further purification.
Reaction SMILES: [Mg].C(Br)C.[C:5]1([C@H:11]([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:21]I.Cl>O1CCCC1>[C:5]1([C@H:11]([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([I:21])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: II
Reactant: C[C@H](Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: C[C@H](Cc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
35 ml of tetrahydrofuran (THF) was added to 11.6 g (0.48 mol) of magnesium, and a solution having 23.6 g (0.22 mol) of ethyl bromide dissolved in 70 ml of THF was dropwise added thereto over a period of 1 hour at room temperature with stirring, followed by stirring for 1 hour. A solution having 50.0 g (0.22 mol) of (R)-2-phenyl-1-(4-chlorophenyl)propane dissolved in 50 ml of THF was dropwise added thereto over a period of 30 minutes at room temperature, followed by stirring under reflux for 5 hours. After the mixture was cooled to room temperature, 250 ml of THF was added thereto, and the mixture was further cooled to −30° C. A solution having 112 g (0.44 mol) of iodine dissolved in 300 ml of THF was dropwise added thereto at −30° C. over a period of 30 minutes, followed by stirring for 1 hour. The temperature was raised to 0° C., and 120 ml of 4M hydrochloric acid was dropwise added thereto, followed by stirring for 10 minutes. After extraction with toluene from the reaction liquid, washing with water and drying were carried out to obtain 69.8 g of (R)-2-phenyl-1-(4-iodophenyl)propane (GC purity: 95.2%, 0.22 mol).
Reaction SMILES: [Li+].[OH-].[C:3]([NH:6][C@@H:7]1[C@H:16]([O:17]C(=O)C)[C@@H:15]([O:21]C(=O)C)[C@H:14]([CH2:25][O:26]C(=O)C)[O:13][C@@H:8]1[O:9]C(=O)C)(=[O:5])[CH3:4]>C1COCC1.O>[C:3]([NH:6][C@@H:7]1[C@H:16]([OH:17])[C@@H:15]([OH:21])[C@H:14]([CH2:25][OH:26])[O:13][C@@H:8]1[OH:9])(=[O:5])[CH3:4]
Reactant: CC(=O)N[C@H]1[C@@H](OC(C)=O)O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@@H]1O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of aqueous LiOH (0.3M, 20 mL) was added dropwise to a solution containing Compound 10 (0.52 g, 1.34 mmol) in THF-H2O (3:1, 22 mL). From TLC, the reaction was complete within 30 minutes. Dowex® 50W-X8[H+] was added to neutralize the solution, then the resin was filtered off, and the filtrate was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (3.5:1) to obtain 0.29 g (1.3 mmol) of Compound 11 (97 percent yield). Further purification was carried out with Bio Gel P-2 chromatography using water as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(I)cc1C(=O)O)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To an ice cooled solution of 2-amino-5-iodobenzoic acid (540 mg, 2.03 mmol) and sodium bicarbonate (170 mg, 2.03 mmol) in 9 mL of dioxane/water (2:1) was added 2,6-dichlorophenylisocyanate (468 mg, 2.44 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was acidified with 2N HCl and extracted with EtOAc. The product, which partially precipitated from the organic layer, was filtered and washed with EtOAc (173 mg). The filtrate was dried (MgSO4) and evaporated under reduced pressure. Trituration of the residue with Et2O afforded an additional 543 mg of 2-[3-(2,6-dichlorophenyl)ureido]-5-iodobenzoic acid: 1H-NMR (300 MHz, d6 -DMSO) δ 7.37 (t, J=8 Hz, 1H), 7.58 (d, J=8 Hz, 2H), 7.84 (dd, J=8 Hz, 4 Hz, 1H), 8.19 (d, J=4 Hz, 1H), 8.28 (d, J=8 Hz, 1H), 9.60 (s, 1H, exchangeable), 10.50 (s, 1H, exchangeable).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH2:25]([NH2:27])C.[OH-].[Na+]>ClCCCl>[CH3:25][NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: CCN
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 103.9 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), ethylamine hydrochloride (0.159 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 126 (0.55 g, 99%) as a semi-solid. 1H NMR (DMSO-d6) δ 1.07 (t, 3H, J=7.2 Hz), 1.47-1.58 (m, 1H), 1.99-2.08 (m, 2H), 2.42-2.59 (m, 3H), 2.67-2.73 (m, 2H), 2.82-2.90 (m, 1H), 6.14 (brs, 1H), 7.81 (s, 1H), 7.86-7.97 (m, 2H), 8.31 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 286 (MH+, 100), 241 (33).
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=[C:18]([F:21])[C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:9])([F:10])[F:8])[C:3]=1[CH2:11][O:12][C:19]1[C:18]([F:21])=[CH:17][C:16]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][C:14]=1[F:13]
Reactant: COC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: OCc1c(C(F)(F)F)nsc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)nsc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (200 mg, 0.76 mmol, 1.00 equiv), methyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (199 mg, 0.92 mmol, 1.20 equiv), PPh3 (401 mg, 1.53 mmol, 2.00 equiv), tetrahydrofuran (3 mL), DIAD (3.9 mg, 0.02 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 190 mg (51%) of methyl 3-(4-[[5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:24]([C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]=1[O:36][Si](C)(C)C)[CH:31]=O)([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=[CH:31][C:30]2[CH:29]=[C:28]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:35]([OH:36])=[C:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=2)[C:7]1=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)CCC1(C)C
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a chilled solution (-70° C.) of 1.657 g (8.95 mmol) of the thus obtained 1-ethoxycarbonyl-5,5-dimethylpyrrolidin-2-one in THF (45 ml) was added 9 ml of a THF solution of 1.0M lithium hexamethyldisilazane under a nitrogen atmosphere. Five minutes later, 2.74 g (9 mmol) of 3,5-di-tert-butyl-4-trimethylsiloxybenzaldehyde was added thereto and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice-water and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate and evaporated to give a residue, which was then dissolved in 40 ml of toluene and combined with 280 mg of p-toluenesulfonic acid and the mixture was refluxed for 1.5 hours. After cooled down, the reaction mixture was evaporated and the resulting residue was dissolved in 30 ml of THF. Under ice-cooling, 3.5 ml of a THF solution of 2.0M tetra-n-butylammonium fluoride was added thereto and the mixture was stirred for 10 minutes. The mixture was poured into ice-water containing sodium bicarbonate and extracted with dichloromethane. The dichloromethane layer was washed with an aq. sodium bicarbonate, water, then saturated brine and dried over magnesium sulfate and evaporated to give 1-ethoxycarbonyl-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one as residue, which was then dissolved in a methanol/water (4/1) mixed solution (100 ml). Five % solution of potassium hydroxide (5 ml) was added thereto while being stirred under ice-cooling and stirred at room temperature for 3.5 hours. The reaction mixture was neutralized with 38 ml of 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was recrystallized from a dichloromethane/ether mixture to give 386 mg of the objective compound. Then the mother liquor was chromatographed on silica gel (toluene/ethyl acetate=1/1) and recrystallized to give 559 mg of the objective compound. Totally, 945 mg of the objective compound was obtained in 24% overall yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH:12]([C:14]([NH2:16])=[O:15])[NH2:13].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:13]/[NH:12][C:14]([NH2:16])=[O:15])/[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C/C(=N\NC(N)=O)c1ccc(F)cc1
Yield: 108 %

Procedure:
To a solution of 1-(4-fluorophenyl)ethan-1-one (27.6 g, 199.80 mmol, 1.00 equiv) and hydrazinecarboxamide hydrochloride (22 g, 197.25 mmol, 0.99 equiv) in methanol (200 mL) was added a solution of sodium acetate (16.8 g, 204.79 mmol, 1.02 equiv) in water (80 mL) dropwise with stirring. The resulting solution was stirred at room temperature for 2 h. The solid was collected by filtration then air-dried to give 41.6 g of crude (E)-2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxamide as a white solid. LCMS (method A, ESI): RT=1.22 min, m/z=196.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])=[N:8]2)=[C:4]([NH2:23])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])[N:8]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:4]([NH2:23])[N:3]=1
Reactant: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2I)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-fluoro-8-(2-iodo-4,5-dimethoxy-benzyl)adenine (12 mg, 0.028 mmol), Cs2CO3 (9 mg, 0.028 mmol), pent-4-ynyl tosylate (8.6 mg, 7 L, 0.036 mmol) in anhydrous DMF (80 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (13.7 mg, 99%) was collected through silica gel column purification (CHC13:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDC13) 7.27 (s, 1H), 6.65 (s, 1H), 5.94 (bs, 2H), 4.29 (s, 2H), 4.13 (t, J=7.3 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.26-2.22 (m, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.97-1.90 (m, 2H); 13C NMR (100 MHz, CDC13) 156.5, 153.2, 151.3, 150.0, 149.1, 130.9, 121.9, 112.6, 88.5, 82.5, 70.0, 56.4, 56.2, 42.6, 39.2, 28.4, 16.1; MS m/z 496.2 (M+H)+. HPLC: (a) 99.9% (60% water-40% acetonitrile); (b) 96.8% (35% to 55% acetonitrile).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH2:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: C=COC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C=COC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
51.5 g of vinyl acetate and 20 g (0.1 mole) of lauric acid were introduced into a 100-ml two-necked round-bottomed flask. The acid was dissolved by warming and 0.4 g of mercuric acetate was added under a stream of nitrogen. The mixture was thus maintained for 30 minutes at ambient temperature, with magnetic stirring, under nitrogen. Two drops of sulfuric acid (95%) were then added and the reaction mixture was heated under reflux for 3 hours. It was then permitted to cool to ambient temperature and 0.21 g of sodium acetate was then added.
Reaction SMILES: [CH3:1][NH2:2].O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][CH2:15][S:16][CH2:17][C:18]1[O:22][C:21]([C:23](OC)=[O:24])=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1.C[O-].[Na+].[ClH:36]>CO>[ClH:36].[NH2:5][CH2:14][CH2:15][S:16][CH2:17][C:18]1[O:22][C:21]([C:23]([NH:2][CH3:1])=[O:24])=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1
Reactant: CN
Reactant: COC(=O)c1oc(CSCCN2C(=O)c3ccccc3C2=O)cc1-c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1oc(CSCCN)cc1-c1ccccc1

Procedure:
Gaseous methylamine was passed into a solution of 5-[[2-(1,3-dioxo-2H-isoindol-2-yl)ethyl]thio]methyl-3-phenyl-2-furancarboxylic acid, methyl ester (4 g) and sodium methoxide (0.01 g) in dry methanol (50 ml). After 4 hours 2 M hydrochloric acid (100 ml) was added and the solution was extracted with diethyl ether (200 ml). The aqueous fraction was basified with 5 M sodium hydroxide (40 ml) and extracted with chloroform (200 ml). The chloroform extract was mixed with 2 M hydrochloric acid (100 ml) and the resulting solid was collected by filtration affording the title compound (1.6 g) as yellow needles. m.p. 189°-190°.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH2:16])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH:16][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(NN)nc2ccccc2c1=O
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCn1c(NNC(=O)CCCl)nc2ccccc2c1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a stirred mixture of 4.50 g of 3-allyl-2-hydrazino-quinazolin-4(3H)-one (0.0208 mol) and 5.75 g of anhydrous potassium carbonate (0.0416 mol; 2 eq) in 100 ml of chloroform at room temperature as added 2.2 ml of 3-chloropropionyl chloride (2.91 g; 0.023 mol; 1.1 eq). Almost immediately, a precipitate appeared and after 1 hr, 50 ml of water were added to the stirred mixture to dissolve any potassium carbonate. The mixture was filtered and the product was washed twice with water then twice with ether, crystallized from ethanol and dried under vacuum over P2O5 at 80° C. to obtain 5.79 g (91% yield) of 3-allyl-2-(2-(3-chloropropionyl)hydrazino)quinazolin-4(3H)-one melting at 151°-153° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 4-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 55 mg (52.8% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>[Cl-].[NH4+].C(Cl)Cl>[N:9]1([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(Cl)n1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Nc1cccc(N2CCOCC2)n1
Temperature: 200 °C

Procedure:
6-Chloropyridin-2-amine (244 mg, 1.90 mmol) and morpholine (0.827 mL, 9.49 mmol) were combined and heated for 2 hr at 200° C. via microwave irradiation. The reaction mixture was diluted with saturated aqueous ammonium chloride and DCM. The organics were separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-80% acetone/hexanes, linear gradient) to afford 6-(morpholin-4-yl)pyridin-2-amine. MS ESI calc'd. for C9H14N3O [M+H]+ 180. found 180. 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=7.9 Hz, 1H), 5.99 (d, J=8.1 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 3.82-3.75 (m, 4H), 3.46-3.38 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([S:44](Cl)(=[O:46])=[O:45])[CH2:42][CH3:43]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([S:44]([CH2:41][CH2:42][CH3:43])(=[O:46])=[O:45])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCCS(=O)(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-D-02, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (40 mg) and propane-1-sulfonyl chloride (0.70 ml) instead of mesyl chloride, a crude product of bis-(4-methoxy-benzyl)-[5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl]-amine was obtained. Using a crude product (12 mg) of this bis-(4-methoxy-benzyl)-[5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl]-amine, the PMB groups were removed according to the above Deprotection method 2, to obtain 5-[2-morpholin-4-yl-7-(propane-1-sulfonyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-ylamine as a colorless powder (5.4 mg, 77%).