Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:32]1[C:40]2[C:35](=[N:36][CH:37]=[N:38][C:39]=2[NH2:41])[N:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)[N:33]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]2[N:34]([C@H:42]3[CH2:47][CH2:46][C@@H:45]([N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)[CH2:44][CH2:43]3)[N:33]=[C:32]([C:19]3[CH:18]=[CH:17][C:16]([CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:21][CH:20]=3)[C:40]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(NC(=O)OC(C)(C)C)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of tert-butyl N-{phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate (3.0 g, 0.00733 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g, 0.0054 mol), tetrakis-(triphenylphosphine)palladium (0.381 g, 0.00033 mol) and sodium carbonate monohydrate (1.69 g, 0.0136 mol) was heated in a mixture of ethylene glycol dimethyl ether (80 mL) and water (40 mL) at 80° C. for sixteen hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (100 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-tert-butyl N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)-methyl]carbamate (2.24 g, 0.00375 mol) as a white solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([S:23][CH3:24])[C:13]=2[C:25]#[N:26])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([S:23][CH3:24])[C:13]=2[C:25]#[N:26])[CH2:9][CH2:10]1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1nc2c(C=O)cnn2c(NC2CC2)c1C#N
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: CSc1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.7 %

Procedure:
Hydantoin (366 mg, 3.7 mmol) and 7-(cyclopropylamino)-3-formyl-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (1 g, 3.7 mmol) were dissolved in ethanol (18.5 mL) along with piperidine (3.7 mL, 3.7 mmol). The reaction was heated at 80° C. After 10 hours, the reaction was cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give the intermediate, 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (1.1 g, 83% yield). LCMS (M+1=356)
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.CCCCCC.[CH2:20]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:21][CH3:22].Br[CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36].Cl>C1COCC1.O>[CH2:20]([O:23][C:24]([C:26]1([CH2:33][CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:21][CH3:22]
Reactant: CCCOC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC(=O)C1(CC(CC)CC)CCCCC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 77.4 %

Procedure:
To a solution of dicyclohexylamine (4.281 g, 23.6 mmol) in THF (27 mL) 1.6 M n-BuLi in hexane (13.22 mL, 21.14 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid n-propyl ester (3.0 g, 17.62 mmol) in THF (9 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C., then 1-bromo-2-ethylbutane (4.072 g, 24.67 mmol) in THF (11.25 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (5.1 g) was distilled at 60° C. (0.05 mbar) to give 3.47 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid n-propyl ester as a colorless oil, purity 97% (GC area). 1H-NMR (CDCl3, 400 MHz): ppm 0.79 (t, 6H), 0.96 (t, 3H), 1.15-1.42 (m, 10H), 1.41-1.43 (m, 2H), 1.52-1.61 (m, 3H), 1.63-1.70 (m, 2H), 2.06-2.14 (m, 2H), 4.0 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:9])[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30].[Cl-].[NH4+]>O1CCCC1>[C:10]1([C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:29]=[O:30])=[CH2:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: C=C(c1ccccc1)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(C=O)c1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 1-bromo-3-(1-phenylvinyl)benzene (1.00 g, 3.86 mmol) in tetrahydrofuran (5 mL) was stirred under a nitrogen atmosphere at −78° C., and 1.6 M n-butyllithium/hexane solution (3 mL, 4.8 mmol) was added dropwise. After 1 hr, N,N-dimethylformamide (0.372 mL, 4.80 mmol) was added, and the mixture was further stirred at the same temperature for 2 hrs. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (0.626 g, yield 78%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].O>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-chloropyridine (3.85 g, 29.95 mmol) and 2-nitrobenzoyl chloride (5.56 g, 29.95 mmol) in pyridine (50 mL) was stirred at 0° C. for 1 h and then at room temperature overnight. Water was added and the precipitate formed was collected by filtration and dried to give N-(2-chloropyridin-3-yl)-2-nitrobenzamide as a white solid (8.52 g, crude yield: >100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[Mg].II.N([P:18]([Cl:20])Cl)(CC)CC>CCOCC.C1COCC1>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[P:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[Cl:20]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: CCN(CC)P(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(P(Cl)c2ccc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.92 ml (2161 mmol) of 4-bromo-1,3-dimethylbenzene in 3 ml of Et2O were added at 0° C. to a suspension of 0.5 g (20.56 mmol) of magnesium turnings in 7 ml of THF and 7 ml of Et2O and also a crystal of iodine. The mixture was heated to room temperature, stirred further overnight and slowly added dropwise at 0° C. to a solution of 1.5 ml (10.31 mmol) of Et2NPCl2 in 8 ml of THF. The mixture was heated to room temperature and the solvent was subsequently removed under reduced pressure. After adding 60 ml of hexane, the mixture was filtered through Celite under argon and admixed with hydrogen chloride for 1 hour. After degassing, the resulting solids were filtered off under argon and dried. Yield: 1.4 g (58.3% of theory). 1H NMR (400 MHz, CDCl3) δ, 7.40 (d, Jmeta=4.5 Hz, 2H, arom.), 7.2 (m, 4H, arom.), 2.5 (d, JPH=2.0 Hz, 6H, CH3), 2.4 (s, 6H, CH3). 31P NMR (161.974 MHz, CDCl3) δ, 75.6.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)[C:21]([CH3:30])=[CH:20][C:18]=1[NH2:19]>CC(O)C.Cl>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:19][C:18]2[CH:20]=[C:21]([CH3:30])[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:23][C:17]=2[CH3:16])=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc(C2CCCCN2)c(C)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (120 mg, 0.49 mmol) and 2,5-dimethyl-4-(piperidin-2-yl)aniline (100 mg, 0.49 mmol) in 2-propanol (10 mL) was treated with conc. aqueous HCl (7 drops). The mixture was sealed and heated in a microwave at 130° C. for 45 min. The mixture was concentrated to afford 5-Chloro-N2-(2,5-dimethyl-4-(piperidin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; ESMS m/z 412.1 (M+H+). The crude product was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C)c(C)c1C(NCc1ccc(OC)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 25.2) and 4-methoxybenzylamine. tR: 3.99 min (HPLC 1); tR: 0.86 min (LC-MS 2); ESI-MS: 428 [M+H]+ (LC-MS 2); Rf=0.59 (EtOAc).
Reaction SMILES: [O:1]=[C:2]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C@@H:3]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:35](=[CH2:45])[CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCCCCC.C(OCC)(=O)C.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>[C:23]([O:22][C:21]([NH:20][C@H:3]([C:2](=[O:1])[N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:35](=[CH2:45])[CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:7][CH:6]=1)=[O:27])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)N1CCCCC1
Reactant: C=C(Br)CCC(=O)OC(C)(C)C
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: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CCC(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
tert-Butyl (S)-(1-oxo-1-(piperidin-1-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate (Compound SP414) (3.00 g, 6.54 mmol) was dissolved in DMF (24.0 ml) and water (6.0 ml), tert-butyl 4-bromopent-4-enoate synthesized by the method described in the literature (Organic Letters, 2011, 13, 5830-5833) (2.31 g, 9.82 mmol), Pd(PPh3)4 (1.13 g, 0.978 mmol) and potassium carbonate (1.81 g, 13.10 mmol) were added and the mixture was stirred at 80° C. for 2 hours. The reaction solution was left to cool, and then diluted with hexane/ethyl acetate (1/1) and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-75:25) to afford the title compound SP415 (2.72 g, 85%).
Reaction SMILES: C[O:2][CH:3](O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].OCC1C=C([N+]([O-])=O)C=CC=1O>>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COc1ccc([N+](=O)[O-])cc1C(O)OC
Agent: O=[N+]([O-])c1ccc(O)c(CO)c1
Product: COc1ccc([N+](=O)[O-])cc1CO
Yield: 76 %

Procedure:
This compound was prepared by reduction of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal using a method similar to that described for preparing 2-hydroxymethyl-4-nitrophenol in 76% yield: MP 121-122° C.; 1H NMR (DMSO-d6, 500 MHz) δ 8.22 (d, 1H, J=1.22 Hz), 8.16 (dd, 1H, J=2.7 and 9.1), 7.16 (d, 1H, J=8.9 Hz), 4.50 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(F)cc1
Temperature: 0 °C
Yield: 34.7 %

Procedure:
A solution of 7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (13.527 g, 54.7 mmol) in concentrated ammonium hydroxide (150 mL, 3852 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled to 0° C. and filtered. The precipitate was consecutively washed with water and dried, first—by passing air through the filter, and then—in pump vacuum to give 7-(4-fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (4.670 g, 18.97 mmol, 34.7% yield). LC-MS (M+H)+=247.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.70-11.81 (2H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95 (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(F)c2o1
Product: Fc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 51.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (107 mg, 0.68 mol) and 2-(but-3-ynyl)-7-fluorobenzo[d]oxazole (128 mg, 0.68 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 94 mg (0.35 mmol, 52%) of 7-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)C>Cl.C(O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(N)cc1
Yield: 95.6 %

Procedure:
Ethyl 2-(4-acetamidophenoxy)propanoate (5.0 g, 2.0 mmol) is hydrolyzed by refluxing for 6 hours at 80° C. with ethanol (10 mL) and 3 drops of concentrated hydrochloric acid. The reaction is concentrated under reduced pressure to obtain ethyl 2-(4-aminophenoxy)propanoate (0.4 g) (yield 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH:27](O)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH3:23].CS(Cl)(=O)=O>CN(C=O)C.O.CCOC(C)=O>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:23]
Reactant: CCC(O)N(CC)CC
Reactant: CC(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1ccc(C(C)=O)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylate of N,N-diethyaminopropanol (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2–3% MeOH/DCM. (yield 50–60%)
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([Cl:20])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 3,3-diphenylpropionic acid (20 g, 88.4 mmol) and thionyl chloride (7.74 mL, 106.1 mmol) is added 5 drops of pyridine. The mixture is stirred at room temperature overnight (15 hours), and then distilled in vacuo to afford a light yellow oil, 17.88 g. The title compound forms as a light yellow solid when the oil is refrigerated overnight; mp 41°-43° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[C:21]([O:23][CH3:24])=[O:22])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of methyl 4-fluoro-3-nitrobenzoate (6.46 g, 32.5 mmole) and methyl piperidine-2-carboxylate (5.57 g, 1.2 equiv) in DMF (80 mL) was added Cs2CO3 (1.2.7 g). The reaction mixture was stirred at 55° C. overnight. The solid was filtered and the filtrate was evaporated. The residue was recrystallized with EtOAc/Hexane to give Methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)piperidine-2-carboxylate (9.4 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1OC
Solvent: O
Product: COc1cc(C(=O)CN2CCN(c3ccncc3)CC2)ccc1OCC(=O)O
Yield: 47 %

Procedure:
In a similar manner to Example 2, but starting from the product of Example 5, the title compound was prepared in 47% yield: m.p. 218°-224° C.; NMR(d6DMSO) δ 8.16(2H,d), 7.65(1H,dd), 7.53(1H,d), 6.92(1H,d), 6.85(2H,d), 4.73(2H,s), 3.86(2H,s), 3.82(3H,s), 3.36(4H,t), 2.63(4H,t); m/e 386(M+H)+ ; calculated for C20H23N3O5. H2O: C, 59.5; H, 6.2; N, 10.4. found: C, 59.5; H, 5.9; N, 10.1%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[N:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[S:11](Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:10][C:4]1[C:5]([Cl:9])=[N:6][C:7]2=[N:8][S:11][N:1]=[C:2]2[N:3]=1
Reactant: Nc1nc(Cl)c(Cl)nc1N
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Clc1nc2nsnc2nc1Cl

Procedure:
The cyclization reaction of o-diaminobenzene (compound II) in an aqueous solution of glyoxal and sodium hydrogen sulfite gives quinoxaline (compound III; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). Quinoxaline is in turn oxidized by an aqueous solution of potassium permanganate to produce 2,3-pyrazinedicarboxylic acid (compound IV; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). 2,3-pyrazinedicarboxylic acid is then chlorinated with phosphorus pentachloride at 300° C. to produce 2,3,5,6-tetrachloropyrazine (compound V; See C. G. Allison et al., J. Chem. Soc. (C), 1970, page 1023). The reaction of 2,3,5,6-tetrachloropyrazine with ammonium chloride at a temperature of 120° C. gives 2,3-diamino-5,6-dichloropyrazine (compound VI; See Palamidess et al., Ed. Sc. XXI-fasc, 11, 1966, page 810). The cyclization reaction of 2,3-diamino-5,6-dichloropyrazine with thionyl chloride in the presence of pyridine in xylene produces 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VII; See Y. C. Tong, J. Heterocyclic Chem., 12, 1975, page 451 ). The 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine is reacted with potassium phthalimide in the presence of dimethyl formamide (DMF) at a temperature of 60° C. to produce 5,6-diphthalimido[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VIII; See Example 1). The 5,6-diphthalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine is then reacted with an aqueous solution of hydrazine at 0° C. to produce 5,6-diamino-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound IX; See Example 2). Finally the cyclization reaction of 5,6-diamino[1,2,5]thiadiazolo[3,4-b]pyrazine with thionyl chloride in the presence of pyridine in methylene chloride gives bis[1,2,5]thiadiazolo[3,4-b:3',4'-e]pyrazine (compound I; See Example 3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:12][C:11]=1[NH:10][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: O=C(Cl)c1cccnc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3cccnc3)c2)cc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 2, pyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-4-cyanobenzamide to give the title compound in 67% yield; NMR Spectrum: (DMSOd6) 7.57 (d, 1H), 7.59 (m, 1H), 7.73 (d, 1H), 8.01 (d, 2H), 8.10 (m, 3H), 8.34 (d, 1H), 8.79 (d, 1H), 9.15 (d, 1H), 10.33 (s, 1H), 10.66 (s, 1H); Mass Spectrum M+H+ 377.