Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>[Pd].C(O)C>[NH2:14][C:3]1[C:2]([CH3:1])=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: [H][H]
Reactant: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC(C)C)c1N
Yield: 96.5 %

Procedure:
The 2-nitrobenzamide of Step D (1.70 g, 7.6 mmol) was hydrogenated over 5% palladium on carbon in 40 mL of ethanol at 345 kPa (50 psi). When the uptake of hydrogen ceased the reaction was filtered through Celite® filter agent and the Celite® was washed with ether. The filtrate was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 41.6 %

Procedure:
A mixture of 0.0398 g (0.00013 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.022 g (0.000143 mole) of 4-amino-3-methylbenzoic acid, 0.7 mL of ethanol, 2.8 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the white precipitate that formed was collected by filtration to give 0.0229 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-56a) as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47](B4OC(C)(C)C(C)(C)O4)=[CH:46][CH:45]=3)=[O:42])=[CH:36][CH:35]=2)=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:3]=[C:2]([C:47]1[CH:48]=[CH:49][C:44]([NH:43][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[O:42])=[CH:45][CH:46]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Reactant: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)c5cc(F)c(-c6cccnc6)cc5n4)cc3)cc2)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline (90 mg, 0.000259 mol), 1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (144.7 mg, 0.0003114 mol), cesium carbonate (212.3 mg, 0.000647 mol), DMF (5 mL) and water (2.5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (9.07 mg, 0.0000131 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (15 mg, 6%) 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 9.0 (s, 1H), 8.93 (brs, 1H), 8.68-8.72 (m, 1H), 7.92-8.73 (m, 5H), 7.52-7.64 (m, 5H), 7.35 (d, J=8.1 Hz, 2H), 3.85 (s, 8H), 3.46-3.57 (m, 4H), 2.24-2.37 (m, 4H), 2.19 (s, 3H); LC-MS (ESI): Calculated mass: 646.2; Observed mass: 647.2 (RT: 0.11 min).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]2C#N)=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:8]3[C:9]([S:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=43)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:20]=1
Reactant: N#CC1Sc2ccccc2N1C(=O)c1ccc(F)cc1
Reactant: COC(=O)C#CC(=O)OC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(4-fluorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (8.1 g, 28.0 mmol) in dichloromethane (50 mL) was added dropwise 8 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (12.2 g, 84.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-fluorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 2.5 g (23%); mp 186-187° C. 1H NMR (DMSO-d6) δ 3.63 (3H, s, COOMe), 3.83 (3H, s, COOMe), 6.78-6.80 (1H, m, ArH), 7.28-7.30 (1H, m, ArH), 7.30-7.44 (3H, m, 3×ArH), 7.62-7.66 (2H, m, 2×ArH), 8.03-8.05 (1H, m, ArH). Anal. Calcd. for (C20H14FNO4S): C, 62.65; H, 3.68; N, 3.65; S, 8.36. Found: C, 62.68; H, 3.46; N, 3.62; S, 8.76.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H-].[Na+].[CH3:14][N:15]([CH:17]=O)C>>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:17]3[N:15]=[CH:14][CH:5]=[CH:4][C:3]=3[C:2]#[N:1])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1cccc2cnccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cccnc1Nc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-amino-isoquinoline (526 mg) in DMF (20 ml) at 0-5° C. was added sodium hydride (400 mg of a 55 to 65% dispersion in mineral oil). The cooling bath was removed and the dark green reaction mixture was stirred at room temperature for 30 minutes. 2-Chloro-nicotinonitrile (506 mg) was added and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by addition of water and the products were extracted several times with EtOAc. The combined organic layers were washed with water and 3M CaCl2, dried (MgSO4) and evaporated under reduced pressure. The remaining red-brown solid material was re-crystallised from ethanol and gave 2-(isoquinolin-5-ylamino)-nicotinonitrile (306 mg): 13C-NMR (DMSO-d6) δ 157.6, 152.4, 152.4, 143.1, 142.5, 135.0, 132.1, 129.0, 127.2, 126.9, 125.1, 116.5, 116.3, 114.3, 92.5.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14]3=[CH:15][N:16]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[N:17]=[C:13]3[CH:12]=[CH:11][N:10]=2)[CH:3]=1.[CH3:26][NH2:27]>CN1C(=O)CCC1>[Cl:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:25])[C:18]=1[N:16]1[CH:15]=[C:14]2[C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:27][CH3:26])[N:7]=[CH:6][N:5]=3)=[N:10][CH:11]=[CH:12][C:13]2=[N:17]1
Reactant: Clc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Reactant: CN
Solvent: CN1CCCC1=O
Product: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 45.3 %

Procedure:
A solution of (6-chloropyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]amine (80 mg, 0.20 mmol) and methylamine (2M in THF, 300 μL, 0.60 mmol) in NMP (2.0 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 160° C. for 30 minutes in the microwave. Further methylamine (300 μL, 0.20 mmol) was added and the reaction mixture was irradiated at 170° C. for 30 minutes. The resultant mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a white solid (35.0 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.03 (br s, 1H), 9.14 (s, 1H), 8.21 (s, 1H), 7.91 (d, J=6.3 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.70 (dd, J=9.0, 7.4 Hz, 1H), 7.23 (br s, 1H), 7.13 (d, J=6.4 Hz, 1H), 2.81 (d, J=4.7 Hz, 3H). LCMS (Method B): RT=2.99 min, m/z: 386 [M+H+].
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15](=[O:16])[CH2:14][CH2:13][C:12]3=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidine-2,5-dione (60 mg, 0.25 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+]([O-])=O)[CH:14]=[N:13][CH:12]=2)[C:4]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[O:24][C:19]3[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=3)=[CH:14][N:13]=[CH:12][C:11]=4[C:5]=2[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cncc3cccc([N+](=O)[O-])c23)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)Oc1cccc3cncc-2c13
Temperature: 80 °C

Procedure:
Phenol 5 (4.65 g, 0.014 mol) was dissolved in 100 ml of dry N,N-dimethylformamide. The solution was degassed with argon for thirty minutes. Potassium carbonate (5.80 g, 0.042 mol) was added to the yellow solution in one portion. After heating at 80° C. for one hour, the mixture had turned brown and no more starting material remained. After the solution was cooled to room temperature, 200 ml of water was added. The aqueous layer was extracted with dichloromethane (3×500 ml), this organic extract was washed with water (3×500 ml), dried (Na2SO4), and concentrated. A white powder (3.65 g 92%) was obtained that was used in the next reaction without further purification. An analytical sample was recrystallized from ethyl acetate:hexane: mp 195-196° C.; 1H NMR: (300 MHz, CDCl3): 9.02 (s, 1H); 8.82 (s, 1H); 7.87 (d, 1H, J=8.7 Hz); 7.62 (m, 3H); 7.32 (dd, 1H, J=6.0, 1.5 Hz); 6.95 (d, J=9.6 Hz); 3.88 (s, 3H); 3.82 (s, 3H). CIMS m/z: 280 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][NH:29][S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4].C(SCC(OC)CNS(CCC[I:64])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:28][NH:29][S:30]([CH2:33][CH2:34][CH2:35][I:64])(=[O:32])=[O:31])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane IIIe4 is allowed to react and worked up by the same procedure as described in (5). m.p. 82°-83° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[OH:25])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[OH:25])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccncc1O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2O)CC1

Procedure:
EXAMPLE 106 was prepared from 4-(3-hydroxy-pyridin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (which was prepared by EDC coupling of 4-amino-pyridin-3-ol and N-benzyloxycarbonyl piperidine-4-carboxylic acid) by borane-THF reduction overnight at room temperature. The reaction was quenched by slow addition of 1N HCl until pH=2, then basified to pH=10 with 10 N NaOH. Extraction with chloroform yielded a crude product which was purified by preparative chromatography, eluting with 90:10 chloroform saturated with ammonia:methanol to give 4-[(3-hydroxy-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester: MS (m+1)=342.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][C:11]1[N:12]=[C:13]([NH:16][C:17](=O)[O:18]C2C=CC=CC=2)[S:14][CH:15]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([NH:16][C:13]2[S:14][CH:15]=[C:11]([CH3:10])[N:12]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Cc1csc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCOC1
Product: Cc1csc(NC(=O)Nc2ccc(F)c(Br)c2)n1

Procedure:
Step 2 A solution of 3-bromo-4-fluoroaniline (250 mg, 1.316 mmol) in THF (6 mL) was stirred on ice and treated with TEA (0.367 mL, 2.63 mmol), then with phenyl 4-methylthiazol-2-ylcarbamate (308 mg, 1.316 mmol) and the resulting solution was stirred at rt for 70 h. The mixture was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, rinsed with water and dried under vacuum to provide 1-(3-bromo-4-fluorophenyl)-3-(4-methylthiazol-2-yl)urea as an off white solid (400 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H) 7.94 (dd, J=6.3, 2.5 Hz, 1H) 7.37-7.45 (m, 1H) 7.32 (t, J=8.7 Hz, 1H) 6.67 (d, J=1.1 Hz, 1H) 2.23 (d, J=1.1 Hz, 3H). Mass spectrum m/z 330, 332 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)CCC>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CCCNC(=O)c1nnc2c(-c3cnccn3)cccc2c1N
Yield: 45.4 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-(tributylstannyl)pyrazine (219 mg, 0.600 mmol) were reacted to afford the title compound (70 mg, 45% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.41 (m, 1H), 8.74 (m, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.54 (br, 1H), 8.22 (m, 1H), 7.99 (m, 1H), 7.85-7.78 (m, 1H), 3.48 (apparent quartet, J=7.0 Hz, 2H), 1.69 (apparent sextet, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H). MS APCI, m/z=309 (M+H) HPLC 1.49 min.
Reaction SMILES: Br[CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].CN(C=[O:26])C>O>[OH:26][CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCC(Br)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Reactant: CN(C)C=O
Solvent: O
Product: CCC(O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
200 mg (581 μmol) 2-bromo-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one are combined with 1.2 ml DMF and 0.8 ml of water. The mixture is stirred for 3 h at 100° C. and then separated by RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:4]2[CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 130 °C
Yield: 8 %

Procedure:
A mixture of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (0.7 g, 3.40 mmol, 1.0 equiv; intermediate B1) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 4.08 mmol, 1.2 equiv) in anhydrous DMF (6 mL) was heated by microwave irradiation to 130° C. for 4 h. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (3:1→1:1) provided 0.1 g (8%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.33-1.45 (m, 2H), 1.47 (s, 9H), 1.97-2.08 (m, 2H), 2.18 (s, 3H), 2.90-2.99 (m, 2H), 4.01-4.08 (m, 3H), 5.19 (br s, 1H), 7.13 (s, 1H), 8.04 (br s, 1H). MS (ISP): 370.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]([CH3:25])([CH3:24])[C@@H:21]([NH2:23])[CH3:22]>C(#N)C>[CH3:19][C:20]([CH3:25])([CH3:24])[C@@H:21]([NH:23][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5])[CH3:22]
Reactant: C[C@H](N)C(C)(C)C
Reactant: O=C(CCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccc(F)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (5.0 g, 0.027 mol) and K2CO3 (7.45 g, 0.054 mol) in acetonitrile (100 mL) was added (S)-3,3-dimethylbutan-2-amine (3.24 g, 0.032 mol), and the reaction mixture was stirred at rt overnight. The solution was filtered, and the filtrate was concentrated to give (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (6.40 g, 94%). 1H NMR (CDCl3): 0.82 (s, 9H), 0.91-0.96 (d, 3H), 2.14-2.22 (m, 1H), 2.73-2.82 (m, 1H), 3.01-3.11 (m, 3H), 7.01-7.09 (m, 2H), 7.88-7.96 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:20][CH:19]([CH2:21][OH:22])[CH2:18][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: OCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCC(O)CO)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 59.9 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (17.4 g, 68.7 mmol) in N,N-dimethylformamide (200 ml) was added glycidol (5.0 ml, 75 mmol) and cesium carbonate (1.55 g, 4.76 mmol). The suspension was heated to 70° C. for 17 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (13.48 g, 41.17 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 1.30 (m, 6H), 2.0-2.1 (m, 2H), 2.24 (m, 1H), 2.49-2.62 (m, 3H), 2.71 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 4.75 (s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 328 [M+H]+, 350 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][C:18]([CH3:26])([CH3:25])[C:19]#[C:20]/[CH:21]=[CH:22]/[CH2:23]Br.Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:23]/[CH:22]=[CH:21]/[C:20]#[C:19][C:18]([CH3:26])([CH3:25])[CH3:17])[CH3:2]
Reactant: CC(C)(C)C#C/C=C/CBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)C)P(=O)(OCC)OCC
Yield: 66.8 %

Procedure:
3.34 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 594 mg of 60% oily sodium hydride is added under ice cooling and stirring, and ethanol solution (10 ml) of 600 mg of (E)-6,6-dimethyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred for 5 hours. The reaction solution is neutralized with 1N hydrochloric acid and then concentrated under reduced pressure, the residue is dissolved in a mixture of water with ethyl acetate, the organic layer is taken and post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 140 g; hexane/ethyl acetate=3/1→1/1] to obtain 686 mg of (E)-diethylphosphono-(6,6-dimethyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[CH3:18][C:19]1[C:23](C#N)=[C:22]([NH2:26])[NH:21][N:20]=1>C(O)(=O)C>[CH3:18][C:19]1[C:23]([C:22]#[N:26])=[C:17]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)[N:21]2[N:20]=1
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: Cc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 24.3 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 150 ml. of glacial acetic acid and 12.2 g. of 3-methyl-5-aminopyrazole-4-carbonitrile is refluxed for 6 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 149°-150° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][O:5][C:4]([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)Br)=[N:3]1.C([O-])([O-])=[O:27].[Na+].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:25])[CH2:6][O:5][C:4]([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)=[O:27])=[N:3]1
Reactant: COc1cc(OC)nc(C(Br)c2ccccc2C2=NC(C)(C)CO2)n1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)nc(C(=O)c2ccccc2C2=NC(C)(C)CO2)n1
Reaction time: 3 h

Procedure:
A mixture of 1.2 g of 2-(2-(4,4-dimethyl-oxazolin-2-yl)-α-bromobenzyl)-4,6-dimethoxy-pyrimidine and 2 g of Na2CO3 in 30 ml of DMSO is heated with stirring at 50°-60° C. for 3 hrs. The mixture is poured into 150 ml of water and extracted with toluene. The toluene extract is washed twice with water (2×50 ml) separated and concentrated. The thus obtained gum is chromatographed with 800 ml of 80/20 hexane/ethyl acetate, 500 ml 70/30 hexane/ethyl acetate, 60/40 ml hexane/ethyl acetate (50 ml fractions) fractions 29 to 34 yielded the title compound.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:15]1(=O)[CH2:20]CC[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:20][CH2:15][CH2:16][CH2:17][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: O=C1CCCCC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CCCC2
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (2.4 g, 0.012 mole), cyclohexanone (1.18 g, 0.012 mole) and ammonia solution (2.0M, 120 mL) in methanol was refluxed overnight. The solvent was removed in vacuo and rhe residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (2.02 g, 94% yield).