Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:29]([C:28]1[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (2.18 g, 7.96 mmol) in 80 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (1.12 mL, 8.00 mmol) and valeryl chloride (0.95 mL, 8.00 mmol) under an atmosphere of nitrogen. After stirring for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was treated with Et2O and filtered. The filtrate was concentrated and the resulting black tar was dissolved in 80 mL of ethanol and treated with 3 mL of triethylamine and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. Chromatography (SiO2, 1–5% methanol (MeOH)/CHCl3) gave tert-butyl N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (1.41 g) as a mauve foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C[O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17]>>[OH:11][CH:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][NH:17][C@H:16]([C:15]([OH:19])=[O:14])[CH3:18]
Reactant: Fc1cc(F)cc(C2CO2)c1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: C[C@H](NCC(O)c1cc(F)cc(F)c1)C(=O)O

Procedure:
Following General Procedure EB and reacting 2-(3,5-difluorophenyl)-1,2-epoxyethane (Example ECl) and L-alanine methyl ester hydrochloride (Bachem), the title compound was isolated after flash chromatography with 3:1 to 1:1 (gradient) hexanes/ethyl acetate.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19]O)=[CH:11][N:10]=1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>ClCCl>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([CH2:19][Cl:23])=[CH:11][N:10]=1
Reactant: OCc1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1nc(N[C@@H]2C[C@H]3CC[C@@H]2C3)ncc1CCl
Temperature: 25 °C

Procedure:
To a mixture of rac-{2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (1.05 g) and dichloromethane (21 mL) was added thionyl chloride (0.8 mL) under ice-cooling, followed by stirring under ice-cooling for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, followed by stirring for 10 minutes. The reaction mixture was extracted with chloroform and the obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain rac-N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (1.06 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:16])[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[O:13][CH:14]=[CH:15][C:8]=3[C:6]=2[N:7]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[O:13][CH:14]=[CH:15][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)-c1ccoc1CCC2
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2occc2-3)cc1

Procedure:
The product from Example 4B (0.06 g, 0.27 mmol) was treated with p-toluenesulfonyl chloride as described in Example 1C to yield the title product: 1H NMR (300 MHz, CDCl3) δ 7.94 (dt, J=8.48, 2.04 Hz, 2H), 7.35 (dd, J=8.48, 0.68 Hz, 2H), 7.31 (d, J=1.7 Hz, 1H), 6.93 (d, J=2.03 Hz, 1H), 4.78 (br s, 2H), 3.01 (t, J=6.61 Hz, 2H), 2.7 (m, 2H), 2.47 (s, 3H), 1.91 (m, 2H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [CH:1](/[C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH:29](/[C@H:33]1[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]1)=[CH:30]\[CH2:31][CH3:32].C(Cl)Cl>CN(C)C1C=CN=CC=1.CCCCCC>[CH:29](/[C@H:33]1[CH2:38][CH2:37][C@H:36]([O:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5](/[CH:1]=[CH:2]/[CH2:3][CH3:4])[CH2:6][CH2:7]2)=[O:13])[CH2:35][CH2:34]1)=[CH:30]\[CH2:31][CH3:32]
Reactant: CC/C=C/[C@H]1CC[C@H](O)CC1
Reactant: CC/C=C/[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC/C=C/[C@H]1CC[C@H](OC(=O)[C@H]2CC[C@H](/C=C/CC)CC2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 200 mg of trans-4-(1E-butenyl)cyclohexanecarboxylic acid, 272.4 mg of dicyclohexylcarbodimide, 13.4 mg of 4-(dimethylamino)pyridine, 169.7 mg of trans-4-(1E-butenyl)cyclohexanol and 4 ml of methylene chloride was stirred at room temperature for 21 hours while gassing with argon. Subsequently, the heterogeneous reaction mixture was diluted with 10 ml of hexane and filtered (rinsing with hexane). The concentrated filtrate was taken up in 30 ml of hexane and the solution was washed in each case once with 30 ml of 5 percent hydrochloric acid, 30 ml of saturated sodium hydrogen carbonate solution and 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the colourless oil (450 mg) on silica gel with ethyl acetate/petroleum ether (vol. 1:99) gave 280 mg (80.1%) of trans-4-(1E-butenyl)cyclohexanecarboxylic acid trans-4-(1E-butenyl)cyclohexyl ester as colourless crystals. Recrystallization from 15 ml of methanol at - 20° C. gave 223 mg of ester as colourless needles with melting point (C-N) 46.3° C. and cl.p. (N-I) 58.7° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.IC.[H-].[Na+].[C:20]([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:20])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(c2ccc(Br)nc2)C(=O)N1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccc(Br)nc2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
(810 mg, 3.0 mmol) 1-(6-Bromo-pyridin-3-yl)-4,4-dimethyl-imidazolidin-2-one (Example 3, step 1) was dissolved in DMF (8 ml) and cooled to 0-5° C. Iodomethane (640 mg, 280 μl, 4.5 mmol, 1.5 equiv.) and NaH (60%) (156 mg, 3.9 mmol, 1.3 equiv.) were added and the mixture was stirred for 2 hours at 0-5° C. The reaction mixture was treated with sat. NaHCO3 solution and extracted two times with EtOAc. The organic layers were extracted with water and brine, dried over Na2 SO4 and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 0:100. The desired 1-(6-bromo-pyridin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (800 mg, 94% yield) was obtained as a yellow solid, MS: m/e=284.1/286.0 (M+M+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:14]=1[C:15]([NH:17][C:18]1([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCOCC1>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:14]=1[C:15]([NH:17][C:18]1([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
To a solution of methyl 4-(1-(2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinamido)cyclopropyl)benzoate (D144) (60 mg, 0.122 mmol) in 1,4-dioxane (3 ml) and water (1 ml) lithium hydroxide monohydrate (7.7 mg, 0.18 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo, and the residue was diluted with water (5 ml) and 1M HCl (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (E7) (racemic mixture) (47 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:11][CH2:12][CH3:13]
Reactant: N#Cc1ccccc1F
Reactant: CCCCN
Product: CCCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and butylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cccnc1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: N[C:2]1[C:3](=[O:12])[NH:4]C=[C:6]([C:8](OC)=O)[CH:7]=1.[Br:13][CH2:14]CCCCC(O)=O>>[Br:13][CH2:14][CH2:8][CH2:6][CH2:7][CH2:2][C:3]([NH2:4])=[O:12]
Reactant: O=C(O)CCCCCBr
Reactant: COC(=O)c1c[nH]c(=O)c(N)c1
Product: NC(=O)CCCCCBr

Procedure:
Solid phase synthesis has been employed in the preparation of certain pyridinones. In Solid Phase Synthesis of 1,3,5-Trisubstituted Pyridin-2-ones, Tetrahedron Letters, 40(1999) 2227-2230 authors James A. Linn et al. report the solid phase synthesis of 1,3,5-trisubstituted pyridin-2-ones via selective NH-alkylation of 3-amino-5-carbomethoxy-1H-pyridin-2-one using a solid supported halo-acid. The synthesis proceeds by the coupling of 6-bromohexanoic acid to a Rink amine macrocrown to form a solid-supported 6-bromohexanamide. The solid-supported 6-bromohexanamide was used to alklylate 3-amino-5-carbomethoxy-1H-pyridin-2-one which was then reacted with diphenylacetic acid. Saponification of the resulting ester yielded a solid supported carboxylic acid. Treatment of the solid supported carboxylic acid with pentafluorophenol provided the pentafluorophenyl ester, which when treated with benzylamine was cleaved from the macrocrown to give the pyridinone. However, a solid phase synthesis procedure to produce ring fused 2-pyridinones has not yet been reported.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[NH:34]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@@H:35]([C:42](O)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CC(C)N=C=NC(C)C>C1COCC1>[C:48]([O:47][C:45](=[O:46])[NH:34][C@H:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:43])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of compound 10A (1.0 g, 2.15 mmol) and BOC-D-Phg-OH (11A, 0.65 g, 2.58 mmol) was added anhydrous THF (30 mL) and the resultant mixture was stirred at rt for 5 min. DIPC (0.40 mL, 2.58 mmol) was added slowly at rt. The final reaction mixture was stirred at rt overnight. The solvent was removed and the residua were dissolved in small amount of ethyl acetate. Solid was removed by filtration. The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1 and 2/3). The product was recrystallized from hexanes-ethyl acetate gave the title compound (12A, 0.81 g) as white crystals in 54% yield. 1H NMR (CDCl3, 500 MHz) δ 10.60 (s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.81 (d, 2H, J=8.0 Hz), 7.77 (s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.41 (m, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 5.58 (d, 1H, J=3.5 Hz), 5.53 (d, 2H, J=3.5 Hz), 4.31 (s, 2H), 4.06 (d, 2H, J=3.5 Hz), 3.86 (d, 1H, J=13.0 Hz), 3.16 (t, 1H, J=13.0 Hz), 2.48 (d, 1H, J=13.5 Hz), 2.00 (s, 1H), 1.61 (br s, 2H), 1.56-1.30 (m, 11H), 0.88 (m, 1H). LCMS (ESI) m/z 720.27 (MNa+), 698.22 (MH+), 642.10, 598.15, 345.16 (100), 289.14. HPLC: tR=5.25 min.
Reaction SMILES: [CH:1](/[C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)=[CH:2]\[CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:53][CH:54]=[CH2:55]>CN(C=O)C>[CH2:55]([O:33][C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]([C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])=[C:11]([N:8]4[CH2:7][CH2:6][C:5](/[CH:1]=[CH:2]/[CH:3]=[CH2:4])([CH3:45])[CH2:10][CH2:9]4)[N:16]3[N:17]=2)[CH:21]=1)[CH:54]=[CH2:53]
Reactant: C=CCBr
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5OCC=C)c4)nn23)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
.(S,E)-Methyl 2-(7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-2-(5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.143 mmol) was dissolved in DMF (3 mL). Solid K2CO3 (39.5 mg, 0.286 mmol) was added and the mixture was heated to 90° C. for 1 h. The reaction was then cooled to rt and treated with 3-bromoprop-1-ene (0.024 mL, 0.286 mmol) and allowed to stir at rt for 18 h. The reaction was partitioned between EtOAc and water. The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated in vacuo to yield (S,E)-methyl 2-(2-(2′-(allyloxy)-5′-chloro-[1,1′-biphenyl]-3-yl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.134 mmol, 94% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (br. s., 1H), 8.07-8.00 (m, 1H), 7.60-7.48 (m, 2H), 7.42 (d, J=2.7 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=17.0, 10.1 Hz, 1H), 6.16 (dd, J=15.5, 10.1 Hz, 1H), 6.08 (s, 1H), 5.98 (ddt, J=17.3, 10.6, 4.8 Hz, 1H), 5.88 (d, J=15.7 Hz, 1H), 5.40-5.33 (m, 1H), 5.25-5.15 (m, 2H), 5.03 (d, J=10.0 Hz, 1H), 5.00-2.50 (m, 4 H), 4.56 (dt, J=4.8, 1.6 Hz, 2H), 3.74 (s, 3H), 2.64 (s, 3H), 1.97-1.63 (m, 4H), 1.32-1.23 (m, 12H). LCMS (M+1)=669.3.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Cl:14])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-3-nitro-5-bromopyridine (10 g) was combined with 25 mL of phosphorus oxychloride and 5 g of phosphorus pentachloride. The mixture was heated to 110° C. for 2 h, then cooled to room temperature and poured into ice-water and stirred 30 min. The mixture was extracted with CHCl3, then the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by chromatography through a short plug of SiO2, eluting with 4:1 hexanes:EtOAc afforded 6.72 g of 5-bromo-2-chloro-3-nitro-pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: FC(F)(F)c1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-trifluoromethyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (87 mg, 70%); 1H NMR δ (CDCl3): 8.75-8.73 (m, 1H), 8.49-8.52 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.23-7.19 (m, 1H), 6.87-6.84 (m, 2H); LCMS m/z: 247.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:21]O>O>[CH3:21][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([O:14][CH3:15])[CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(C(C)(C)C)c(OC)c1

Procedure:
To a solution of 4-tert-butyl-3-methoxy-benzoic acid (3.00 g, 14.4 mmol; commercially available from Apin, 41226B) in MeOH (30 mL) is added H2SO4 conc. (3 mL) and the mixture is refluxed for 5 hrs. After cooling, the mixture is diluted with water, extracted twice with diethyl ether, the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound as yellowish oil. MS: 223.0 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.12 min. 1H-NMR (CDCl3): δ 1.41 (s, 9H), 3.91 (s, 3H), 3.92 (s, 3H), 7.36 (dd, 1H), 7.54 (d, 1H), 7.60 (dd, 1H) ppm.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]3[C:13]([NH:16][C:25](=[O:26])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:17]3)=[CH:14][CH:15]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Yield: 14 %

Procedure:
A solution of 15 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine and 12.5 parts of diethyl 2-oxo-1,3-propanedioate in 80 parts of ethanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 3.1 parts (14.0%) of ethyl 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-3-oxo-2-quinoxalinecarboxylate; mp. 229.7° C. (comp. 107).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1.Cl.CN(C)[CH2:21][CH2:22][CH2:23][N:24]=[C:25]=NCC.N1CCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][C:2]1([CH3:1])[CH2:15][C:6]2=[C:7]([C:12]([N:24]3[CH2:25][CH2:21][CH2:22][CH2:23]3)=[O:14])[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CC(C)(C)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a stirred solution of 6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylic acid (1.0 g, 3.7 mmol), 4-dimethylaminopyridine (0.75 g, 6.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) in DCM (30 mL) was added pyrrolidine (0.34 mL, 4.1 mmol). The mixture was stirred for 18 h then the solution was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic later was separated, washed with 1M HCl (2×20 mL) and sat. K2CO3 (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was titurated with hexane/ether to afford the title amide (905 mg, 76%) as a colourless solid. mp 153-155° C. C16H21NO2S2 requires: C, 59.41; H, 6.54; N, 4.33%. Found: C, 59.70; H, 6.73; N, 4.77%. 1H NMR (360 MHz, CDCl3) δ 1.05 (6H, s), 1.94-2.04 (4H, m), 2.40 (2H, s), 2.59 (3H, s), 2.84 (2H, s), 3.59-3.62 (4H, m). MS (ES+) 324 (M+1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][CH3:21])=[CH:24][CH:25]=1)=[O:6])#[N:2]
Reactant: CSc1ccc(S)cc1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CSc1ccc(SC[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethyl-amide (258 mg) and cesium carbonate (329 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-(methylsulfanyl)thiophenol (162 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone. The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on a silica gel (using 9:1 dichloromethane: acetone as the eluent) provided the title compound as a white solid. 1H NMR (DMSO-d6): δ=8.63 (1H, t), 7.24 (2H, d), 7.18 (2H, d), 4.13 (2H, d), 2.97 (1H, dd), 2.58 (1H, m), 2.96 (3H, s), 2.1 (2H, m), 1.7 (4H, m), 1.2 (4H, m) MS [ESI, (M−H)−] m/z=332.8 amu
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:12]
Reactant: O=C1CCCN1
Reactant: O=C=NCCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)NCCCl
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 65.1 g (765 mmol) of 2-oxopyrrolidine and 67.3 g (638 mmol) of chloroethyl isocyanate was heated with stirring at 95°-105° C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting compound obtained from the eluate with toluene-ethyl acetate (20/1-10/1 v/v) was recrystallized from CH2Cl2 -ether-n-hexane, whereby 107.7 g of the objective compound 1-(2-chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) melting at 66.5°-67.5° C. was obtained as crystals.