Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A mixture of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (518 mg, 1.28 mmol/g, 0.66 mmol) in 8 mL of DMF is shaken at room temperature for 15 minutes, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (400 mg, 3.75 mmol/g, 1.5 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide (21 mg, 23%) as a solid. MS: 277 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][S:29](=[O:32])(=[O:33])[CH2:30][CH2:31]2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cn1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
[6-(Dimethylamino)-3-pyridinyl]boronic acid (34 mg, 0.202 mmol), 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (75 mg, 0.202 mmol) and potassium carbonate (84 mg, 0.606 mmol) were suspended in 4 mL of dioxane:water (3:1) and degassed for a few minutes with nitrogen gas. Pd(PPh3)4 (23 mg) was then added and the reaction mixture was heated in a microwave oven at 150° C. for 40 minutes on ‘high’ absorption setting. After heating, LCMS of all crude reaction mixtures showed the desired m/z with few impurities. The crude reaction mixtures were filtered through 500 mg Stratospheres SPE Thiol cartridges eluting with 10 mL methanol/DCM (1:1) and concentrated. The residues were dissolved in DMSO (˜3 mL) and purified via RP-HPLC using an XBridge Prep C18 column with water/acetonitrile (0.1% NH4OH buffer). The desired fractions were concentrated, giving 0.029 g (34.8%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[SH:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[S:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ncccn1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ncccn3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyrimidine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.CCC[CH2:14][CH:15]([C:18](O)=[O:19])CC.COC(OC)(C(C1C=CC=CC=1)=O)C1C=CC=CC=1.C(O)(=O)C=C.C(OCCO)(=O)C=C>>[C:18]([O:10][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:19])[CH:15]=[CH2:14]
Reactant: CCCCC(CC)C(=O)O
Reactant: CCCCCC#CC(=O)O
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCO
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Product: C=CC(=O)OCCCCCCCC

Procedure:
The acrylic monomers generated in Examples 1 and 10-12, 2-OA, 2-EHA, and LA were each prepared into adhesive films using the following procedure. The alkyl acrylate (28.5 g), 0.02 g of IRGACURE 651 (Ciba), 0.3 g of acrylic acid (AA, Alfa Aesar), and 1.2 g of hydroxyethyl acrylate (HEA, Aldrich) were mixed using a magnetic stir bar in a clear glass vial. The glass vial was then purged with nitrogen for 5 minutes to remove dissolved oxygen, and then treated with UV light (365 nm, approximately 5 mW/cm2) until a coatable viscosity was achieved. The target for this step was an approximate viscosity of 3000 cP at room temperature and acrylic conversion of approximately 10%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([CH3:20])([CH3:19])[CH:6]=[C:5]2[CH3:21].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([B:27]([OH:30])[OH:28])=[CH:11][CH:10]=2)[C:5]([CH3:21])=[CH:6][C:7]1([CH3:20])[CH3:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COB(OC)OC
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Yield: 43.8 %

Procedure:
A 25 mL r.b. flask, equipped with a magnetic stirring bar, was charged with Compound 8 (3.765 g, 10.67 mmol) under N2. The oil was dissolved in 11 mL THF (anhydrous) and cooled to -78° C. tert-Butyllithium (12.6 mL, 21.4 mmol, 1.70M) was added by syringe over a period of 10 min (maintaining temperature below -70° C.) turning the reaction mixture from pale yellow to bright yellow. The reaction was allowed to continue at -75° C. until all of the starting material had been consumed as judged by TLC (15% ethyl acetate/hexane). Trimethyl borate (1.22 g, 1.33 mL, 11.7 mmol, 1.1 equiv) was added by syringe over 5-10 minutes (temperature between -70° C. and -65° C.). The reaction was monitored by TLC. Upon completion, the product mixture was quenched with saturated NH4Cl (200 mL). Addition of ethyl acetate (200 mL) partitioned the mixture into 2 phases. The organic phase was washed with saturated NH4Cl (100 mL) and brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined and dried (Na2SO4). The crude mixture was applied to a small column containing 200 mL silica and 15% ethyl acetate/hexane. The higher Rf impurities were eluted with 2 L of 10% ethyl acetate/hexane. The boronic acid, Compound 9, was eluted with 500 mL ethyl acetate followed by 750 mL ethanol to provide 1.483 g (44%) of Compound 9. Data for Compound 9: 1H NMR (400 MHz, acetone-d6) 7.73 (d, J=1.2, 1H), 7.66 (dd, J=8, 1.2, 1H), 7.13 (d, J=8, 1H), 5.49 (s, 1H), 2.01 (d, J=1.6, 3H), 1.50 (s, 9H), 1.46 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:3]1[C:4](=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:1][C:2]1=[O:12]
Reactant: CI
Reactant: O=C1NC(=O)C2(CCCCC2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)NC2(CCCCC2)C1=O
Temperature: 50 °C

Procedure:
1,3-diazaspiro[4,5]decane-2,4-dione (4.0 g 0.078 mole) J. Prakt. Chem. 141 5-43 (1934) was added to a suspension of sodium hydride (1.14 g 50% oil dispersion) in dimethylformamide and heated at 50° C. for 1 hour, cooled, methyl iodide added (1.63 ml. 1.1 eq) and the mixture heated at 50° C. The dimethylformamide was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic extract was washed with water, dried (MgSO4), evaporated to dryness and the crystalline residue crystallised from ethyl acetate-light petroleum (40°-60° C.) to give the title compound as white prisms m.p. 214°-215° C. Yield 2.6 g=39%.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:15]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:18][C:11]=2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1nc2sc(C3CCC(C)(C)CC3)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 130 °C

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (30.0 g) and toluene (240 mL) were added phosphorous oxychloride (40 mL) and DMF (1.0 mL), followed by heating to reflux at 130° C. for 2 hours. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue were added chloroform and saturated aqueous sodium bicarbonate, followed by stirring. The organic layer was washed sequentially with water and brine. To the organic layer were added MgSO4, activated carbon (10 g), and silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.3 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc([N+](=O)[O-])c1O
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (5.00 g, 25.3 mmol) in concentrated H2SO4 (98%, 10 mL) was added concentrated HNO3 (63%, 10 mL) dropwise. The mixture was stirred at −40° C. for 10 min. The mixture was poured into ice-water and extracted by EA (3 times). The organic layers were combined, dried over anhydrous Na2SO4. Then the solvent was evaporated in vacuo to afford 3-hydroxy-2-methyl-4-nitrobenzoic acid as a yellow solid, which was used for next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2(O)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=1)[NH:21][CH:20]=[CH:19]2.FC(F)(F)C(O)=O.[Cl-].[NH4+]>ClCCl>[CH:1]1([C:4]2([C:19]3[C:18]4[C:22](=[C:23]([CH2:25][S:26][CH3:27])[CH:24]=[C:16]([F:15])[CH:17]=4)[NH:21][CH:20]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: OC1(C2CC2)CCc2cc(F)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
633 mg (2.47 mmol) of the compound from Example 76A with a purity of 75% and 530 mg (2.71 mmol) of the compound from Example 11A were introduced into 12 ml of dichloromethane at 0° C., 0.23 ml (2.96 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 0° C. for 4 h. It was diluted with dichloromethane and added to saturated aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 570 mg (63% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([C:6]1[C:7]([C:22](OCC)=[O:23])=[N:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.[CH3:28][NH:29][NH2:30]>C(O)C.O>[CH3:28][N:29]1[C:22](=[O:23])[C:7]2=[N:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:27])[CH3:1])=[N:30]1
Reactant: CNN
Reactant: CCOC(=O)c1nn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Solvent: O
Solvent: CCO
Product: CC(C)Cc1nn(C)c(=O)c2nn(Cc3cccc4ccccc34)cc12

Procedure:
A mixture of ethyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-3-carboxylate (0.15 g) and methylhydrazine (0.1 ml) in ethanol (2 ml) was heated at reflux for 18 hours. The reaction was diluted with water and then extracted into ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated. The residue was chromatographed, eluting with dichloromethane:ethanol (19:1), to give the title compound (0.08 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:20]=1)([O-:30])=[O:29]
Reactant: Nc1ccc2c(c1)OCc1cc([N+](=O)[O-])ccc1C2=O
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(Nc3ccccc3[N+](=O)[O-])ccc21
Temperature: 100 °C

Procedure:
In accordance with general method Z, 1.00 g (3.70 mmol) of (6), 0.80 g (3.96 mmol) of 1-bromo-2-nitrobenzene, 2 spatula tips of Pd(OAc)2, 0.10 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphine ligand), 0.70 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out and dissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at 100° C. under an argon atmosphere for 4 h. The crude product is purified by chromatography over silica gel with MC/EtOH (98/2). Yield 0.35 g (24.2%); melting point: 212.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10](O)=[O:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].B>C1COCC1>[CH3:1][S:2]([C:5]1[S:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: B
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CO)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a THF (3 mL) solution of 5-methanesulfonyl-thiophene-2-carboxylic acid (900 mg, 4.32 mmol) at RT was added borane in THF (1M solution, 6 mL) and the reaction was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched with methanol. The solvent was evaporated under reduced pressure and the mixture was purified on a silica gel column to afford (5-methanesulfonyl-thiophen-2-yl)-methanol (500 mg, 60.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C@@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.C(O)(=O)C>Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C@@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:24][CH:25]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1CCc1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@@H]2CCN[C@H](CCc3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
(2R,4R)-Methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (507 mg, 1.46 mmol) (from example 92, step 3) was dissolved in hydrogen bromide (33% in acetic acid (11.5 mL, 65.49 mmol) to give a yellow solution. The mixture was stirred at room temperature for 16 h, the solvent was removed and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4R)-2-(4-fluorophenethyl)piperidin-4-yl)isoxazol-3(2H)-one (278 mg, 65%). 1H NMR (400 MHz, cd3od) δ 1.48 (q, 1H), 1.70 (dq, 1H), 1.78-1.96 (m, 2H), 2.09-2.17 (m, 1H), 2.26-2.34 (m, 1H), 2.66-2.80 (m, 2H), 2.86-3.09 (m, 3H), 3.35-3.43 (m, 1H), 5.52 (s, 1H), 6.98-7.05 (m, 2H), 7.21-7.26 (m, 2H). HRMS Calculated for [C16H19FN2O2+H]+: 291.1509. Found: 291.1483
Reaction SMILES: [CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:8]1[CH:29]=[C:28]([O:30][CH3:31])[C:11]2[N:12]([CH2:24][CH2:25][O:26][CH3:27])[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:14][C:10]=2[C:9]=1[CH:33]=[CH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(Cc3ccccc3)cc(OC)c21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1c(Cc2ccccc2)cc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC

Procedure:
A mixture of 300 mg (0.556 mmol) 5-benzyl-4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 40 mg bis(triphenylphosphine) palladium (II) dichloride and 0.2 ml tributyl(vinyl)stannane in 3 ml THF is stirred at reflux temperature for 24 h. The reaction mixture is concentrated in vacuo and the residue is purified by flash-chromatography on silica gel (hexane:EtOAc=6:1) to afford 278 mg of the title compound as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cccc(C#Cc2c[nH]c(C)n2)c1
Reactant: Fc1ccnc(Cl)c1
Product: Cc1cccc(C#Cc2cn(-c3ccnc(Cl)c3)c(C)n2)c1

Procedure:
The title compound, light brown solid, MS: m/e=308.2, 310.1 (M+H+) was prepared in accordance with the general method of example 1b from 2-Methyl-4-m-tolylethynyl-1H-imidazole and 2-chloro-4-fluoropyridine
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1>C(O)(=O)C>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCC1CCOCC1
Solvent: CC(=O)O
Product: O=C1CNc2ncc(Br)nc2N1CC1CCOCC1
Yield: 68.1 %

Procedure:
A stirred solution of ethyl 2-(5-bromo-3-((tetrahydro-2H-pyran-4-yl)methylamino)pyrazin-2-ylamino)acetate (1.474 g, 3.95 mmol) in acetic acid (13 mL) in a sealed vessel was heated at 120° C. in an oil bath for 2 h. The acetic acid was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, shaken and the layers separated. The water layer was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in dichloromethane and hexane and the resulting solids collected by vacuum filtration. The solids were washed with hexane and dried under vacuum to give the desired product (0.879 g, 2.688 mmol, 68% yield) as a purple solid. MS (ESI) m/z 327.1 [M]+, 329.0 [M+2]+.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([CH2:10][OH:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]1[C:9]2[CH:8]=[C:7]([CH:10]=[O:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1
Reactant: OCc1cc2c(cn1)COC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of 1,3-dihydrofuro[3,4-c]pyridin-6-ylmethanol (66 mg, 0.437 mmol) in DCM (5 ml) at rt under argon was treated with manganese dioxide (380 mg, 4.37 mmol) and then stirred at rt for 2 h, filtered through a thin pad of Kieselguhr, eluting with DCM (40 ml) and methanol (10 ml), the organic extracts were evaporated to give the crude product as a brown oil (65 mg, 100%)
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2>O>[N+:14]([C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]#[N:2])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2)([O-:16])=[O:15]
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Solvent: O
Product: N#CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Yield: 78.9 %

Procedure:
At room temperature, 23.3 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine and 35.0 g of hydroxylamine-orthosulfonic acid are agitated in 400 ml of water for 24 hours. The precipitate is suctioned off, washed with water, and recrystallized from ethyl acetate, thus obtaining 16.0 g of 2-(7-nitro-1H-indazol-4-yl)acetonitrile, mp 198°-200° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([S:38]([CH2:41][CH2:42][NH:43][CH2:44][CH2:45][CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:32]1([S:38]([CH2:41][CH2:42][N:43]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH3:49])[CH2:50][CH3:51])(=[O:40])=[O:39])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCN(CC)CCCNCCS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: CCN(CC)CCCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N′-(2-benzenesulfonyl-ethyl)-N,N-diethyl-propane-1,3-diamine (139 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 730 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[NH:26]1>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH3:31])[N:26]1[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: ClCCOc1ccc(COc2ccc(Cl)c3ccccc23)cc1
Product: CC1CCCC(C)N1CCOc1ccc(COc2ccc(Cl)c3ccccc23)cc1
Yield: 47.2 %

Procedure:
A stirred mixture of 0.4 grams (0.001 mole) of 2-chloro-1-(4-((4-chloronaphthyloxy)methyl)phenoxy)ethane and 5 mL (0.037 mole) of cis-2,6-dimethylpiperidine was heated to just below reflux for about 72 hours. After this time, the reaction mixture was analyzed by thin layer chromatography (TLC), which indicated the reaction was incomplete. The reaction mixture was concentrated under reduced pressure and subject to column chromatography on silica gel, yielding 0.2 gram of compound 106. The NMR spectrum was consistent with the proposed structure.