Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][N:13]3[CH:16]=[CH:17][N:18]=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:16]1[N:13]2[N:14]=[CH:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)=[CH:11][C:12]2=[N:18][CH:17]=1
Reactant: Fc1ccc(-c2cnn3ccnc3c2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cnn3c(Br)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.12 mL, 2.34 mmol) was added dropwise to a stirred mixture of 7-(4-fluorophenyl)imidazo[1,2-b]pyridazine (500 mg, 2.34 mmol) and sodium acetate (289 mg, 3.52 mmol) in Acetic Acid (12 mL) and the mixture was stirred at room temperature for 1 h. The mixture was poured into ethyl acetate and aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 9.10 (d, 1H); 8.49 (d, 1H); 7.98 (dd, 2H); 7.96 (s, 1H); 7.38 (t, 2H). LRMS (APCI) calc'd for (C12H8BrFN3) [M+H]+, 292.0. found 292.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18]O)=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=S(Cl)[Cl:23]>>[Cl:20][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:17]([CH2:18][Cl:23])=[CH:16]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Product: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure C using (2-(2-chlorophenyl)-8-chloroquinolin-3-yl)methanol (0.675 g, 2.22 mmol) and SOCl2 (0.81 mL). 8-Chloro-3-(chloro-methyl)-2-(2-chlorophenyl)quinoline was obtained as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1 H, s), 7.88 (1 H, dd, J=8.2, 1.2 Hz), 7.81 (1 H, dd, J=7.4, 1.2 Hz), 7.48 (1 H, d, J=7.4 Hz), 7.42-7.46 (1 H, m), 7.27-7.41 (3 H, m), 4.63 (1 H, d, J=9.8 Hz), 4.33-4.45 (1 H, m) Mass Spectrum (ESI) m/e=322.0 and 324.0 (M+1)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:41]([OH:46])(=[O:45])[CH2:42][CH:43]=[CH2:44].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[CH2:42][C:41]([OH:46])=[O:45])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCC(=O)O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 57.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole (3.0 g) and 3-butenoic acid (1.0 g) in acetonitrile (15 mL) were added triethylamine (2.4 g), palladium acetate(II) (0.11 g) and tris(2-methylphenyl)phosphine (0.29 g), and the mixture was refluxed overnight under shading the light. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give the title compound (1.74 g).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[N:9]=[CH:10][CH:11]=[CH:12][C:5]=2[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1.N1C=CC=CC=1.[C:25]12([CH2:35][C:36](Cl)=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>C(Cl)Cl.CCOC(C)=O>[C:25]12([CH2:35][C:36]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[N:9]=[CH:10][CH:11]=[CH:12][C:5]=4[C:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:3]3)=[O:37])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2cccnc2c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2cccnc2c1=O
Yield: 72.6 %

Procedure:
A mixture of Example 7B (34.8 mg, 0.146 mmol), pyridine (0.014 mL, 0.18 mmol), and (adamantan-1-yl)acetyl chloride (35.2 mg, 0.165 mmol) in CH2Cl2 (0.45 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (3% MeOH/CH2Cl2) to give the title compound (43.9 mg, 0.106 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.15 (dd, 1H), 8.16 (dd, 1H), 7.94 (dd, 1H), 7.65-7.54 (m, 5H), 2.08 (s, 2H), 1.95 (s, 3H), 1.74-1.53 (m, 12H); MS (DCI) M/Z 432.2 (M+NH4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[N:7][CH:8]=2)=[N:24][CH:25]=1
Reactant: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of tert-butyl 4-(5-ethynylpyridin-2-yl)piperazine-1-carboxylate (509 mg, 1.77 mmol), 2-Bromo-5-trifluoromethylpyridine (400 mg, 1.77 mmol), triethylamine (0.74 mL, 5.31 mmol), and cuprous iodide (135 mg, 0.71 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (102 mg, 5 mol %). The reaction was then stirred for 1 hour. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×10 mL). The residue was then dissolved in CH2Cl2 (10 mL) and washed with water (10 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to give tert-butyl 4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (729 mg, 1.68 mmol, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:14]=[C:11]1[NH:12][CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])[CH:3]=2)[CH2:10]1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (4R)-4-(3-amino-4-chlorophenyl)pyrrolidin-2-one (0.18 g, 0.86 mmol), methyl 2-bromobenzoate (0.37 g, 1.72 mmol), palladium acetate (0.038 g, 0.172 mmol), and Buchwald's reagent (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) (0.122 g, 0.256 mmol) was added dioxane (2 mL). The mixture was degassed by alternatively applying a vacuum and flushing with nitrogen for a few cycles. After 15 minutes, potassium carbonate (0.237 g, 1.72 mmol) was added. The mixture was stirred overnight at 100° C., and then cooled to room temperature and filtered through Celite. The filtrate was washed with an aqueous HCl solution and extracted with ethyl acetate (3 times). The ethyl acetate layers were then washed with brine and concentrated to give the title compound (13a) as a brown residue which was used directly in the next step. MS (ESI) m/z 345 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]([CH3:22])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][N:15]=[CH:16][CH:17]=2)[N:12]2[N:19]=[N:20][N:21]=[C:11]2[CH:10]=1>C(O)(=O)C>[CH3:5][CH:6]([CH3:22])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][N:15]=[CH:16][CH:17]=2)[N:12]2[N:19]=[N:20][N:21]=[C:11]2[C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(C)CNc1cc2nnnn2c2cnccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2cnccc12

Procedure:
Nitric acid (2 equivalents of 16M) was added to a solution of N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine (2.0 g, 8.26 mmol) in acetic acid. The reaction mixture was heated on a steam bath for about an hour then concentrated under vacuum. The residue was poured into ice water and the resulting mixture was neutralized with sodium bicarbonate. The resulting precipitate was extracted with dichloromethane. The dichloromethane extracts were combined, washed with water, and dried over magnesium sulfate. Thin layer chromatography indicated a mixture so the material was filtered through a layer of silica gel eluting with 5% ethyl acetate in dichloromethane. The reaction was rerun on 4 g of starting material but using only one equivalent of nitric acid. The resulting material was also a mixture. The material from both reactions was combined then purified by flash chromatography eluting with mixtures of hexanes/ethyl acetate. The fractions containing the slower moving material were combined to provide about 0.3 g of N5-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine as a yellow solid, m.p. 173-174° C. Analysis: Calculated for C12H13N7O2: %C, 50.17; %H, 4.56; %N, 34.13. Found: %C, 49.85; %H, 4.53; %N, 34.26.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([C:35]#[N:36])=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:19]1[CH2:20][C:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[N:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[NH:18]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C#N)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyano-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M184) (295 mg, 0.562 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (125 mg, 55%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[O:7]([CH2:14][CH:15]([OH:17])[CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:4]([O:17][CH:15]([CH3:16])[CH2:14][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CC(O)COc1ccccc1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OC(C)COc1ccccc1

Procedure:
In a similar manner, diketene was reacted with 1-phenoxy-2-propanol to obtain 1-methyl-2-(phenoxy)ethyl acetoacetate, BP 115°-122° C./0.05-0.1 mm.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.Cl.[Cl-].[CH2:46]([N:48]1[CH:52]=[C:51]([CH2:53][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:50]=[N:49]1)[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:46]([N:48]1[CH:52]=[C:51](/[CH:53]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:50]=[N:49]1)[CH3:47]
Reactant: CCn1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4cnn(CC)c4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.50 g), [(1-ethyl-1H-pyrazol-4-yl)methyl]triphenylphosphonium chloride hydrochloride (2.29 g), anhydrous potassium carbonate (1.42 g) and N,N-dimethylformamide (30 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (3:7 to 1:1, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxy phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (446 mg, yield 26%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 140-141° C.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[C:49]([C:64]2[O:65][CH:66]=[CH:67][CH:68]=2)=[C:50]([CH3:63])[C:51]([C:61]#[N:62])=[C:52]2[C:56]=1[O:55][C:54]([C:57]([CH3:60])([CH3:59])[CH3:58])=[N:53]2.[CH3:69][N:70]([CH3:76])[C@H:71]1[CH2:75][CH2:74][NH:73][CH2:72]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:57]([C:54]1[O:55][C:56]2[C:52](=[C:51]([C:61]#[N:62])[C:50]([CH3:63])=[C:49]([C:64]3[O:65][CH:66]=[CH:67][CH:68]=3)[C:48]=2[N:73]2[CH2:74][CH2:75][C@H:71]([N:70]([CH3:76])[CH3:69])[CH2:72]2)[N:53]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: Cc1c(-c2ccco2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccco2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 13.5 %

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (10.4 mg, 16.7 μmol) was dissolved in toluene (0.5 ml) under heat, cooled to room temperature, palladium(II) acetate (2.5 mg, 11.1 μmol) was added, followed by stirring for 1 minute. This was put into a toluene (0.5 ml) suspension of 7-bromo-2-tert-butyl-6-(2-furyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-10) (40 mg, 111 μmol), (3S)-3-(dimethylamino)pyrrolidine (16.9 μl, 134 μmol), sodium tert-butoxide (15.0 mg, 156 μmol), followed by stirring at 80° C. for 17 hours. After cooling, brine (30 ml) was added to the reaction liquid, the product was extracted with chloroform (30 ml×3). The organic layer was washed with saturated brine (30 ml), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→100:1) to obtain the entitled compound (5.9 mg, 13%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:48]([C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[C:57]2=[O:64])=[CH:52][CH:51]=1)#[N:49]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:61]([CH:58]1[CH2:59][CH2:60][N:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]#[N:49])=[CH:51][CH:52]=2)[C:57]1=[O:64])=[O:62]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 3.4 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.434 mmol), PyBOP (0.340 g; 0.651 mmol), N,N-diisoprpylethylamine (0.224 mL; 1.30 mmol) and 1-(4-cyanophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.434 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified preparative HPLC (method 1) to yield 0.006 g (3%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: C=C(C)OC
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Agent: CS(=O)(=O)O
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S,2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2C12 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2C12 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+260.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26])[CH2:7][CH2:6]2)#[N:2].Cl>O1CCOCC1>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[CH:8]1[CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with tert-Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-oxopiperazine-1-carboxylate (450 mg, 1.3 mmol) was added 4N HCl in dioxane. The mixture was allowed to stir at RT for 1 hour. LC showed complete reaction. The volatiles were removed under reduced pressure, and the resulting solids were used without further purification. LC-MS (IE, m/z): 256 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38]=[C:39](B(O)O)[CH3:40]>CN(C=O)C.O>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[CH:3][C:2]([C:39]([CH3:40])=[CH2:38])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: C=C(C)B(O)O
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
A mixture of 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (103 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol, EMD) and prop-1-en-2-ylboronic acid (52.4 mg, 0.610 mmol) in DMF (1.8 mL) and Water (0.2 mL) was degassed by vacuum and purged with Argon. To the resulting mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (16.72 mg, 0.020 mmol, Aldrich) and then heated under microwave conditions at 120° C. for 20 min. The reaction mixture was concentrated in vacuo to a brown solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in hexanes) to yield 25 mg of desired product as a light yellow solid. MS (ESI) 467 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]([OH:11])[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:11][C@@H:4]1[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[CH2:3]1
Reactant: C1=COCCC1
Reactant: CC1=C(C)C(C)(C)C[C@@H](O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C)C(C)(C)C[C@@H](OC2CCCCO2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 g (5.2 mmol) of (1S)-3,4,5,5-tetramethyl-3-cyclohexen-1-ol prepared in Example 2A was dissolved in 5 ml of absolute methylene chloride under N2, the solution was cooled to 0° C., and then firstly 260 mg (1.04 mmol) of pyridinium p-toluenesulfonate and then 450 mg (6.2 mmol) of 3,4-dihydropyran were added. The mixture was subsequently stirred at 0° C. for 1 h and then poured into saturated NaHCO3 solution and extracted with methylene chloride. The extract was dried over MgSO4 and concentrated to result in 1.1 g (corresponding to 89% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:13]1(C)C=CC=CC=1>CO>[NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1ccccc1
Reactant: CC(C)(N)CC(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-3-methyl-butyric acid 10-1 (1 eq.) in methanol at 0° C. was added 2 eq. of thionyl chloride. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated to give azeotropic mixture of 10-2 and toluene (x=3) which was used for Step B. MS: MH+=132.1
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]#N)=[CH:14][CH:13]=1.S(=O)(=O)(O)O.COS(OC)(=O)=O>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Cn1c([N+](=O)[O-])cnc1COc1ccc(SC#N)cc1
Agent: O=S(=O)(O)O
Solvent: COS(=O)(=O)OC
Product: CSc1ccc(OCc2ncc([N+](=O)[O-])n2C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5.8 g (0.02 mols) of 1-methyl-2-(4-thiocyanatophenyloxymethyl)-5-nitro-imidazole are introduced portionwise while stirring, under a nitrogen atmosphere, at room temperature, into a mixture of 26.5 ml of concentrated sulfuric acid and 5.0 g (0.04 mol) of dimethylsulfate and allowed to stand overnight at room temperature. The solution is then heated to 60° C. for 30 minutes, cooled and poured onto ice/water. The precipiate is suction-filtered and washed with water. In addition to bis-4,4'-(1-methyl-5-nitro-imidazolyl-2-methoxy)-diphenyl disulfide (m.p. 160° C.), column chromatographical purification on silica gel yields the 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 116° C.