Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][CH:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[S:31][CH:32]=[CH:33][C:23]=2[NH:22]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]2[C:23]3[CH:33]=[CH:32][S:31][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:21]2[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC1Nc2ccsc2-c2ccccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3C2C)cc1
Yield: 55.9 %

Procedure:
A solution of 4-Methoxybenzenesulfonyl chloride (16 g, 77 mmol), triethylamine (25 mL, 180 mmol), and 4-dimethylaminopyridine (0.20 g, 1.6 mmol) in methylene chloride (100 mL) was de-gassed with nitrogen and treated with a de-gassed methylene chloride (100 mL) solution of 5-Methyl4,5-dihydrothieno[3,2-c]isoquinoline (16 g obtained above) at 23° C. After 21 h the reaction mixture was quenched with 1 N aqueous sodium hydroxide (200 mL). The organic layer was separated and the aqueous phase was extracted with methylene chloride (2×200 mL). The combined extracts were washed with 1 N aqueous sodium hydroxide, 1 N aqueous hydrochloric acid, and brine (200 mL each), dried (K2CO3), and concentrated in vacuo to give the crude product (21 g) as a dark oil. The oil was taken up in methylene chloride (ca. 80 mL) and pre-adsorbed on silica gel (80 g). Flash chromatography on silica gel (400 g) eluting 25-, then 50-, and then 75% methylene chloride-hexane gave the product (16 g) as a yellow solid. Further elution with methylene chloride, then 10-, and then 20% ethyl acetate-methylene chloride gave recovered 5-methylthieno[3,2-c]isoquinoline (1.7 g, 14%) from the previous step. Recrystallization of the product from hot ethyl acetate-hexane provided the title compound (15 g, 79% overall based on recovered starting material from Step 1, m.p. 135-36° C.) as shiny yellow-orange prisms.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:12]=[N:13][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.CCN(C(C)C)C(C)C.[O:41]1[CH2:44][C:43](=O)[CH2:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CO.ClCCl>[CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:12]=[N:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH:43]5[CH2:44][O:41][CH2:42]5)[CH2:19][CH2:18]4)=[CH:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C4COC4)CC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
(R)-4-((R)-1-((3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (130 mg, 0.31 mmol) was dissolved in THF (7.71 ml), followed by the addition of Hunig's base (0.05 ml, 0.31 mmol), 3-oxetanone (0.2 ml, 3.08 mmol), sodium triacetoxyborohydride (228.79 mg, 1.08 mmol) and stirred at 50 C for 90 minutes. The reaction was diluted with 25% methanol/dichloromethane, washed with water, dried, filtered and concentrated. Residues were purified by silica gel column chromatography to yield the (R)-4-((R)-1-((3-methyl-6-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (32.9 mg, 22%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][O:54][C:55]([CH3:59])([CH3:58])[CH2:56][OH:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:57][CH2:56][C:55]([CH3:59])([CH3:58])[O:54][NH:53][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:17]
Reactant: CC(C)(CO)ON
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC(C)(C)CO)cnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.6 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (737 mg, 1.4 mmol), HOBt (231 mg, 1.7 mmol), and EDCI (327 mg, 1.7 mmol) in DMF (15 mL) was added a solution of 2-aminooxy-2-methyl-propan-1-ol hydrochloride (280 mg, 2.0 mmol), and DIPEA (603 μL, 3.6 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 days then diluted with water (30 mL) and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic fractions were filtered through a hydrophobic frit and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (420 mg, 49%). LCMS (Method B): RT=3.47 min, [M+H]+=606.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([CH:11]([CH3:13])[CH3:12])[C@H:6]([OH:14])[CH2:5]2.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1.O>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([CH:11]([CH3:12])[CH3:13])[C@H:6]([O:14][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:20]=1)[CH2:5]2
Reactant: CC(C)[C@@H]1c2ccc(Cl)cc2C[C@H]1O
Reactant: BrCc1cccc(Oc2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H]1c2ccc(Cl)cc2C[C@H]1OCc1cccc(Oc2ccccc2)n1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of trans-5-chloro-1-isopropyl-2-indanol (0.75 g) in anhydrous tetrahydrofuran (5 ml) was added to a suspension of sodium hydride (0.28 g, oil free) in anhydrous tetrahydrofuran (5 ml). The mixture was stirred for 0.5 hr and 2-(bromomethyl)-6-phenoxypyridine (1 g) in anhydrous tetrahydrofuran (5 ml) was added, followed by a catalytic amount of tetra-n-butylammonium iodide. The mixture was stirred at room temperature for 18 hours, mixed with water (100 ml) and extracted with diethyl ether (3×50 ml). The ether extract was dried (MgSO4) and condensed under reduced pressure to give an oil that was purified by flash chromatography to give trans-5-chloro-1-isopropyl-2-((6-phenoxypyridin-2-yl)-methoxy)indane (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([Cl:24])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CC(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To the solution of 1-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (50 mg, 0.158 mmol) in DCM (1.5 mL), was added thionyl chloride (0.1 mL, 1.378 mmol) dropwise. The mixture was stirred at room temperature for 1 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (50 mg, 95% yield). LCMS: rt=3.63 min, [M+H+]=299
Reaction SMILES: [OH-].[Li+].[C:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:13]=2[C:14]([O:16]CCC2C=CC=CC=2)=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>O.O1CCCC1.CO>[C:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:13]=2[C:14]([OH:16])=[O:15])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(OCCc2ccccc2)c(C(=O)OCCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=Cc1ccc(OCCc2ccccc2)c(C(=O)O)c1
Reaction time: 3 h

Procedure:
Lithium hydroxide (4.32 g, 0.18 mol, 3 eq) in water (80 mL) was added to a stirred solution of 2-phenylethyl 2-(2-phenylethoxy)-5-formylbenzoate (22.46 g, 0.06 mol, 1 eq) in a mixture of tetrahydrofuran (240 mL) and methanol (80 mL). The reaction mixture was stirred for 3 h, then concentrated in vacuo, and the residue diluted with water (100 mL), and washed with ethyl acetate (2×100 mL). The aqueous solution was acidified to pH 1 with concentrated HCl, extracted with ethyl acetate (2×100 mL), and the organic solution dried over sodium sulfate and evaporated. This gave a gummy solid, which was recrystallized from ethyl acetate and ether to give a pale yellow powder (8.87 g, 55% (2 steps)). RF (petroleum ether:ethyl acetate, 2:1) 0.35. 1H NMR (CDCl3) δ9.97 (s, 1H, O═C—H), 8.65 (d, 1H, J 2.3 Hz, ArH), 8.11 (dd, 1H, J 8.7 and 2.3 Hz, ArH), 7.18 (d, 1H, J 8.7 Hz, ArH), 4.58 (t, 2H, J 6.8 Hz, OCH2CH2Ph), 3.27 (t, 2H, J 6.8 Hz, OCH2CH2Ph).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=3)[C:6]=2[CH:20]=1.[C-:25]#[N:26].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[N:13]=[CH:14][C:15]([CH2:18][C:25]#[N:26])=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC#N)cn1
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of 6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromehyl)-1H-benzimidazole (from step 5, 550 mg, 1.5 mmol) in DMF (5 ml) and water (1 ml) was added KCN (470 g, 7.2 mmol) at room temperature, and then the reaction mixture was stirred for 2h. The mixture was diluted with water and extracted with ethyl acetate/toluene (4/1) solution (3×30 ml). The organic layer was washed with water, dried (MgSO4) and concentrated. This was purified by SiO2 column chromatography developing with hexane/ethyl acetate (1/) gave 198 mg (37%) of title compound as orange oil.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[OH:11]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:4]1(=[O:11])[O:3][C:1](=[O:2])[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: O=C1OCc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: N#Cc1ccccc1
Product: O=C1OC(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture of 2 mmole of phthalide, 2 mole % of N-hydroxyphthalimide relative to phthalide, and 5 ml of benzonitrile was stirred for 12 hours at 100° C. under an oxygen atmosphere. The products in the reaction mixture were analyzed by gas chromarography, and, as a result, phthalic anhydride (yield 46%) was formed.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[N:43]1[CH:48]=[CH:47][C:46]([C:49](O)=[O:50])=[CH:45][CH:44]=1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: O=C(O)c1ccncc1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)c2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and pyridine-4-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.02 minutes; C31H33ClN6O3 (573.10); mass spectrum: (M−H)−=572.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28](OC4C=CC=CC=4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1.C(OC(C)C)(C)C>C(#N)C>[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:26]([O:27][C:28]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[O:29])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:37])=[N:15]2)=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: O=C(OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Yield: 47 %

Procedure:
Anhydrous piperazine (5.15 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.2 g.) in acetonitrile (32 cc.). The reaction mixture is stirred for 1 hour at a temperature of about 20° C. and diisopropyl ether (150 cc.) is then added. The insoluble product is filtered off and washed with a mixture (20 cc.) of acetonitrile and diisopropyl ether (50--50 by volume) and then with diisopropyl ether (50 cc.). After recrystallisation of the product thus obtained from a mixture (160 cc.) of acetonitrile and methanol (90--10 by volume), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(piperazin-1-yl)carbonyloxy-isoindolin-1-one (2.4 g.), melting with decomposition at 245° C., is obtained.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
(191) A solution of 2-(oxazol-5-yl)pyridine (116 mg, 0.79 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.87 mmol, 0.35 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.58 mmol, 3.2 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.79 mmol, 151 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with hexanoic acid (2 equiv, 1.58 mmol, 186 mg, 0.20 mL) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 8.0 mmol, 1.02 g, 0.70 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of hexanoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)hexan-1-one (191) (50 mg, 0.20 mmol, 25% yield) as a light brown powder: mp 49-50.5° C.; 1H NMR (CDCl3, 250 MHz) d 8.64 (br d, J=3.9 Hz, 1H), 7.85-7.75 (m, 3H), 7.32-7.26 (m, 1H), 3.09 (t, J=7.7 Hz, 2H), 1.82-1.70 (m, 2H), 1.40-1.31 (m, 4H), 0.89 (t, J=6.95 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 181.5, 150.3, 146.2, 143.0, 139.3, 130.0, 119.8, 117.0, 113.3, 32.0, 24.2, 16.6, 15.3, 6.8; IR (KBr) umax 2957, 2872, 1700, 1677, 1603, 1426, 1387 cm−1; MALDI-FTMS (DHB) m/z 245.1284 (C14H16N2O2+H+ requires 245.1284).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1F
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat pyridin-3-amine (82 mg, 0.87 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 85; 200 mg, 0.58 mmol), EDC (223 mg, 1.16 mmol) and HOBT (178 mg, 1.16 mmol) in dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at 25° C. overnight. Water (25 ml) was added into the reaction mixture. The precipitate was filtered, washed with water (15 ml), and dried in vacuum to obtain crude product, which was purified with Prep-TLC (eluate: dichloromethane:methanol=25:1) to yield the title compound as a white solid. 67 mg.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:19][CH2:20][CH:21]([OH:44])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[N:38]([CH3:42])[CH:37]=[N:36][C:35]=2[N:34]([CH3:43])[C:32]1=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH2:11]([O:19][CH2:20][C:21](=[O:44])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[N:38]([CH3:42])[CH:37]=[N:36][C:35]=2[N:34]([CH3:43])[C:32]1=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOCC(O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCOCC(=O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.03 h
Yield: 43 %

Procedure:
Dimethylsulfoxide (0.18 ml, 2.5 mmol) was added slowly by syringe to a stirring solution of oxalyl chloride (0.11 ml, 1.3 mmol) in dichloromethane (5 ml) at -780° C. After 2 minutes, a solution of 1-(11-octyloxy-10-hydroxyundecyl)-3,7-dimethylxanthine, prepared above (0.5 g, 1.0 mmol) in dichloromethane (15 ml) was added dropwise over 5 minutes. Stirring was continued at -78° C. for 45 minutes . Triethylamine (0.72 ml, 5.2 mmol) was added and the cold bath subsequently removed. After 20 minutes, water (25 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (20 ml) and saturated aqueous salt solution (20 ml), and then dried over sodium sulfate. The solvents were evaporated under vacuum to give a thick oil which was purified by chromatography (silica/dichloromethane-5% methanol) to obtain 205 mg of 1-(11-octyloxy-10-oxoundecyl)-3,7-dimethylxanthine (43% yield).
Reaction SMILES: [C:1](#N)[CH3:2].Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.C(N(CC)CC)C>Cl[Pd]Cl.O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH:1]=[CH2:2])[CH:14]=[CH:13]2
Reactant: CC#N
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=Cc1ccc2cc(OC)ccc2c1
Reaction time: 0.5 h

Procedure:
A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 19.45 kg of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BMN) formed as described in Example 7 hereof, and 4.8 g of PdCl2. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 5.3 kg of ACN and 5.64 kg of triethylamine (TEA). The agitator is set at 158 rpm and the reactor is pressured and vented three times with 80 psig nitrogen. The reactor is then purged for ten minutes with nitrogen. Next a mixture of 48.6 g of neomenthyldiphenylphosphine (NMDP) dissolved in 0.35 kg of TEA is charged to the reactor. The agitator is set to 412 rpm and the reactor is heated with steam on the jacket. The reaction temperature is initially in the range of 91°-109° C., while the pressure varies from 412°-519 psig. The reaction produces a heat kick, and after 30 minutes the temperature rises to 109° C. with 26° C. cooling water on the jacket. The total reaction time is 1.75 hours with a BMN conversion of 100%. The reactor is cooled, vented, and the reactor contents are transferred to a 30-gallon glass lined reactor for workup.
Reaction SMILES: [Na].[C:2]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)(=[O:4])[CH3:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14]C)=[O:12].OS(O)(=O)=O>CO>[O:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:2](=[O:4])[CH2:3][C:10](=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 35.4 %

Procedure:
(see, e.g., Ghosh, A. K., et al., J Med Chem 2005, 48, 6767-71). To a stirred solution of MeOH (150 mL) at room temperature under nitrogen, freshly cut Na (1.81 g, 78.7 mmol) was added in pieces and with care. After all the sodium dissolved, a mixture of 2-acetylfuran (6 mL, 59.8 mmol) and diethyl oxalate (8.14 mL, 59.9 mmol) was added dropwise over a period of 3 min at room temperature. The resulting mixture was continued to stir. Brown precipitates formed after 20 min stir. The mixture was stirred for a total of 1 h. The reaction mixture was cooled to 0° C., and a mixture of concentrated H2SO4 and ice was added. Some solid precipitated at this point which was filtered off but was not the desired product by 1H NMR. The filterate was extracted with CH2Cl2 (50 mL×2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was recrystallized from hot iPrOH to give the title compound (4.15 g, 35%) as a dark brown solid. 1H NMR (400 MHz, CDCl3) δ 7.67-7.65 (m, 1H), 7.33 (d, J=3.6 Hz, 1H), 6.93 (s, 1H), 6.60 (dd, J=3.5, 1.5 Hz, 1H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 181.01, 165.39, 162.43, 150.82, 147.73, 118.58, 113.14, 99.17, 53.18.
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:14][C:3]1[CH:2]=[N:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc(-c2ccccc2)cn1
Reaction time: 6 h
Yield: 75 %

Procedure:
To a stirred solution of 3-bromo-5-phenyl-2-amino pyrazine (80 mg; 0.32 mmol), in ethyl acetate (1 mL) was added triethylamine (139 μL; 1.0 mmol) and Pd(OH)2 (10 mg; 20% wt on carbon). The reaction was placed under a hydrogen atmosphere at 45 psi and shook for 6 hours. The reaction was filtered and concentrated under reduced pressure. The product was purified using a biotage 12L eluting with ethyl acetate to yield an off white solid (75% yield).