Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:46]([NH:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])[CH3:47]>>[CH:46]([NH:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([N:58]2[CH2:63][CH2:62][N:61]([C:21]([N:11]3[C@@:12]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)([CH3:13])[C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([CH3:38])[N:9]=[C:10]3[C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[O:22])[CH2:60][CH2:59]2)[CH2:54][CH2:53]1)=[O:51])([CH3:48])[CH3:47]
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)NC(=O)N1CCC(N2CCNCC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCN(C(=O)NC(C)C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperazin-1-yl-piperidine-1-carboxylic acid isopropylamide trifluoroacetate to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). LR-MS: 786.0 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([OH:13])=[CH:11][CH:10]=[N:9][C:8]=12)([O-])=O.C1CCCCC=1.[ClH:20]>[Pd].C(O)(=O)C>[ClH:20].[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:12]([OH:13])=[CH:11][CH:10]=[N:9][C:8]=12
Reactant: O=[N+]([O-])c1cnn2c(O)ccnc12
Agent: [Pd]
Agent: Cl
Solvent: C1=CCCCC1
Solvent: CC(=O)O
Product: Nc1cnn2c(O)ccnc12

Procedure:
0.35 g of 3-nitropyrazolo[1,5-a]pyrimidin-7-ol, 20 cc of acetic acid, 1.6 g of cyclohexene and 85 mg of 10% palladium-on-charcoal were introduced into a 50 cc 3-necked round-bottomed flask fitted with a magnetic stirrer and equipped with a condenser and a thermometer. The medium was refluxed for 1h30' and the catalyst was then filtered off through Celite. After evaporation of the acetic acid, the solid obtained was taken up in 2 cc of refluxing concentrated hydrochloric acid for 2 h 30'. After evaporation of the solvent, an off-white solid was collected.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C@@H:6]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C@H:7]2[CH2:10][OH:11])[O:3]1.C([O-])(=O)C.[Na+].[Br-].[K+].[Cl-].[Na+].O.ClO.[Na].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:1]=[C:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C@@H:6]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C@H:7]2[CH:10]=[O:11])[O:3]1
Reactant: O=C1C[C@@H]2[C@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: OCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Yield: 81.5 %

Procedure:
To a solution of (1S,5R,6R,7R)-3-oxo-6-hydroxymethyl-7-(2-tetrahydropyranyloxy)-2-oxabicyclo[3.3.0]octane (140.5 g; J. Am. Chem. Soc., 98, 1490 (1971)) in ethyl acetate (4100 ml), water (410 ml), sodium acetate (134.9 g), potassium bromide (6.53 g) and 2,2,6,6-tetramethyl-1-piperidinyloxyradical (TEMPO; 2.14 g) were added. The mixture was cooled with sodium chloride-water. The reaction mixture was stirred vigorously. Thereto, a solution of 10% sodium hypochlorous acid (302 ml) which was saturated with sodium hydrogencarbonate was added at a dropwise for 40 minutes. After reaction, the organic layer was washed by an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (113.6 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.[OH:11][OH:12]>CC(C)=O>[CH3:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:10][CH:9]=1.[OH:11][OH:12]
Reactant: COc1ccc(CO)cc1
Agent: OO
Solvent: CC(C)=O
Product: COc1ccc(C=O)cc1

Procedure:
11.15 g of anise alcohol, 39 g of acetone, 2 g of catalyst and 2 cc of 36% w/v aqueous hydrogen peroxide are placed in the glass flask. Operating at 80° C., 3 g of anisaldehyde are obtained (H2O2 yield 94%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]3[N:13]([N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]=3[C:17]([NH2:19])=[O:18])[C:7]=2[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].O1CCOCC1.[ClH:39]>>[Cl:39][CH2:3][CH2:2][C:1]([N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]3[N:13]([N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]=3[C:17]([NH2:19])=[O:18])[C:7]=2[CH2:6]1)=[O:4]
Reactant: Cl
Reactant: C=CC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCN(C(=O)CCCl)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
7-Acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (40 mg, 0.09 mmol) was suspended in Sat. HCl (gas)/dioxane (50 mL), then the mixture was stirred RT for about 1.5 hr, and concentrated to dryness. The residue was suspended into 2 mL of MeOH and 2 mL of water. The organic layer was discarded, aqueous layer was lyophilized to get 40 mg (90%) of 7-(3-chloropropanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.79-11.76 (m, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.04 (m, 4H), 4.71-4.70 (m, 2H), 3.85-3.79 (m, 4H), 3.02 (t, J=6.4 Hz, 2H), 2.79-2.69 (m, 2H). MS (ESI) m/e [M+1]+ 463.8, 465.8.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[NH:19]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[N:3]=[C:2]2[N:19]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20]2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Cn2c(Br)nc3ccccc32)cc1
Reactant: C1CNCCCNC1
Product: Fc1ccc(Cn2c(N3CCCNCCC3)nc3ccccc32)cc1
Temperature: 80 °C
Yield: 108.3 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenylmethyl)-1H-benzimidazole (10.07 g) and 1,5-diazacyclooctane (5.60 g) was heated at 80° C. for 1 hour. To the reaction mixture was added distilled water (300 ml), and the mixture was extracted with methylene chloride (300 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane (12.1 g) as a colorless oily liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[N:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2]
Reactant: COC(=O)CCn1ccc(-c2ncccc2COc2cnc(OC)cc2C=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccn(CCC(=O)O)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To methyl 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (72 mg, 0.18 mmol, 1 eq.) in a mixture of MeOH/THF (1/6, 6.0 mL) was added NaOH (3 N, 0.6 mL, 1.8 mmol, 10 eq.). The mixture was stirred at rt for 2 h, acidified to pH 3, extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-(3-(3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoic acid (53.4 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.57 (d, J=4.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.23 (dd, J=7.9, 4.6 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 5.64 (s, 2H), 4.42 (t, J=6.1 Hz, 2H), 3.83 (s, 3H), 2.86 (t, J=6.1 Hz, 2H). LRMS (M+H+) m/z 383.1.
Reaction SMILES: [C:1]([C:3]1[CH2:4][CH:5]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:6](C(=O)C(F)(F)F)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)#[N:2].Cl>ClC(Cl)C>[NH2:2][CH2:1][C:3]1[CH2:4][CH:5]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1
Reactant: COC(=O)CC1CC(C#N)=Cc2ccccc2N1C(=O)C(F)(F)F
Agent: Cl
Solvent: CC(Cl)Cl
Product: COC(=O)CC1CC(CN)=Cc2ccccc2N1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
nBu4NBH4 is added at ambient temperature to a solution of the compound obtained in Step f (0.792 g; 2.34 mmol) in dichloroethane (10 ml). The reaction mixture is then heated at 45° C. for 8 hours. 10 ml of HCl (10%) are subsequently added and heating is carried out for 1 hour at 50° C. After concentration, the residue is chromatographed on silica (CH2Cl2/EtOH/NH4OH) to yield the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-formylbenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.98 (s, 1H), 8.21 (d, 1H), 8.05 (s, 1H), 7.95 (s, 3H), 7.82 (d, 1H), 7.60 (m, 3H), 7.00 (d, 1H), 6.58 (s, 1H), 6.40 (s, 1H), LC-MS: 370 (MH+); HPLC RT: 4.83 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6]([OH:8])=O.[CH2:13]([N:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:22]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:21][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[NH2:12])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NN(Cc1ccccc1)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1cc(F)c(F)cc1C(=O)NN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 157.5 %

Procedure:
4,5-Difluoroanthranilic acid (4.73 g, 27.3 mmol) and N,N-dibenzylhydrazine (8.69 g, 42 mmol) are combined in 200 mL of methylene chloride. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (7.85 g, 41 mmol) is then added to this solution, and the mixture is stirred for 18 hours at 25° C., The solution is washed with saturated NaHCO3, brine, and dried over magnesium sulfate. The solution is concentrated to give 15.8 g of a dark oil and purified via chromatography (SiO2, CHCl3) to give 3.4 g of the title compound as a solid. MS CI: m/z 368 (MH+).
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=O)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[CH:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1cccc2c1CCc1ccccc1C2=CCCN(C)C
Temperature: 45 °C
Reaction time: 10 h

Procedure:
10 g. of Gilman alloy are covered with 30 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, 40 ml. of 1-chloro-3-dimethylaminopropane in 120 ml. of dry ether are added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is heated at 45° C. under reflux conditions for an additional 3 hours, then cooled with ice water and treated dropwise over a period of one hour with a solution of 21.8 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (J. Med. Pharm. Chem. 4, 335-49, 1961) in 400 ml. of dry ether. Subsequently, the mixture is stirred at 45° C. under reflux conditions for an additional 10 hours, then cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is removed by separation. The aqueous phase is shaken twice with 100 ml. portions of ether and the combined ether extracts are dried over sodium sulfate and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene has a melting point of 154°-155° C. after recrystallization from high-boiling petroleum ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](Cl)=[O:7].[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COCCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.06 g (22.1 mmol) of chloroformic acid (2-methoxy-ethyl) ester in 18 ml of dioxane is added to 2.59 g (22.1 mmol) of L-valine in 26.4 ml of 2N NaOH and the mixture is then stirred for 18 h at RT. The reaction mixture is extracted with chloroform, and the inorganic phase is acidified with 4N HCl and extracted again with chloroform. The chloroform phase last obtained is dried and concentrated by evaporation to yield the title compound: 1H-NMR (200 MHz, CDCl3): 0.92 and 0.99 (2 d, J=7 Hz, 6H), 2.2 (m, 1H), 3.38 (s, 3H), 3.59 and 4.24 (2m, each 2H), 4.3 (m, 1H), 5.4 (d, J=9 Hz, HN), 8.5 (sb, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6](C)=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:21]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: CC(O)c1occc(=O)c1OCc1ccccc1
Product: COC(C)c1occc(=O)c1OCc1ccccc1
Yield: 92.3 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) yielded the title compound as a yellow oil (2.4 g, 92.3%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product (2.1 g, 80.8%) as a bright yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1COCC1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccccn2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
4-Hydroxybenzonitrile (1.00 g, 8.39 mmol) was dissolved in anhydrous DMSO (5.0 mL) and was slowly added a solution of potassium tert-butoxide in THF (1.0 M, 16.8 mmol). The solution was stirred for 2 hours 30 minutes. A solution of 2-bromopyridine (2.65 g, 16.8 mmol) in DMSO (5.0 mL) was then added to the reaction mixture the whole was heated at 160° C. for 115 hours. The cooled mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude solid was placed on a silica gel column and purified (EtOAc/Hex 1:6) to give the product as a light yellow solid (1.04 g, 63%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.01 (1H, d, J=8.2 Hz), 7.10 (1H, dd, J=7.2, 5.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.68 (2H, d, J=8.8 Hz), 7.77 (1H, ddd, J=8.3, 7.3, 2.0 Hz), 8.22 (1H, dd, J=5.0, 2.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 108.0, 112.8 (CH), 118.9, 120.0 (CH), 121.6 (CH), 134.1 (CH), 140.2 (CH), 147.9 (CH), 158.2, 162.5. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0715.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:19][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:22])[C:14]([CH:16]2[CH2:17][CH2:18]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CC2)c1
Reaction time: 1 h
Yield: 654.4 %

Procedure:
A mixture of 10.33 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclopropanecarboxamide and 1.92 g of 60% sodium hydride in oil in 50 ml of dimethylformamide was stirred for one hour under argon, then cooled in an ice bath. A solution of 0.81 g of methyl iodide in 10 ml of dimethylformamide was added dropwise. The mixture was then stirred at room temperature for 0.5 hour and extracted three times with hexane. The mixture was diluted with water and this mixture extracted with dichloromethane. This extract was evaporated and the residue crystallized from hexane, giving 10.17 g of the desired compound, mp 120°-122° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:24][N:8]([CH2:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: Fc1cc(CBr)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2cc(F)c(F)c(F)c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 3,4,5-trifluorobenzylbromide (248 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.078 g (19.7%); MS m/z: 396.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.64 (s, 2H); 4.66 (s, 2H); 6.71-6.74 (m, 2H); 7.13-7.20 (m, 6H); 7.35 (d, 1H, 3J=8.2 Hz); 7.94 (s, 1H); 12.03 (br s, 1H); HPLC (METHOD [A]): rt 18.63 min (92.1%)
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOCC2)c1
Temperature: 180 °C

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.3904 g, 2.154 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.783 g, 3.23 mmol), and cesium carbonate (2.106 g, 6.46 mmol) in N-Methyl-2-pyrrolidinone (7.18 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 180° C. for 30 min. Reaction was worked up via seperatory funnel. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 15% to 100% over 15 min. Further purification was pursued by absorbing crude product onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 404.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:27][CH:28]([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CC#N>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([O:29][CH:28]([F:27])[F:37])=[CH:31][CH:32]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
4-Chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (80 mg, 0.2 mmol) and 4-(difluoromethoxy)-aniline (64 mg, 0.4 mmol) were mixed in MeCN (2 mL).
Reaction SMILES: C(O[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[N+:14]([O-:16])=[O:15])C.[N:17]12[CH2:24][CH2:23][CH2:22][C:21]1([CH2:25][NH2:26])[CH2:20][CH2:19][CH2:18]2>>[N:17]12[CH2:24][CH2:23][CH2:22][C:21]1([CH2:25][NH:26][C:4]1[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=1[N+:14]([O-:16])=[O:15])[CH2:20][CH2:19][CH2:18]2
Reactant: CCOc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: NCC12CCCN1CCC2
Product: O=[N+]([O-])c1c(NCC23CCCN2CCC3)ccc2ccccc12
Yield: 39.1 %

Procedure:
2-Ethoxy-1-nitronaphthalene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 39.1%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[Li]CCCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15].[Cl-].[Li+]>O1CCCC1>[N:5]([CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(CN)OC
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CN([Si](C)(C)C)[Si](C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 128.3 %

Procedure:
Under a nitrogen atmosphere, 5.25 g (0.05 moles) of aminoacetaldehyde dimethylacetal were dissolved in 50 ml of dry tetrahydrofuran and cooled to −78° C. 20 ml of 2.5M nBuLi (0.05 moles) were then added over 5 minutes with stirring. The mixture was then stirred for 15 minutes at −78 C then allowed to slowly warm to room temperature. 6.3 ml (0.05 moles) of chlorotrimethylsilane were then added over 20 minutes and the reaction allowed to stir for an additional 30 minutes. During this addition the mixture increased in temperature and a precipitate of lithium chloride was observed to form. The mixture was then cooled back down to −78 C and an additional 20 ml of 2.5M nBuLi added over 5 minutes with stirring and the mixture was held at this temperature for an additional 15 minutes before being allowed to warm back up to room temperature. An additional 6.3 ml of chlorotrimethylsilane was then added over a 20 minute period with stirring, during which time the mixture was observed to warm up and additional lithium chloride form. The Mixture was then stirred for an additional 30 minutes before being filtered. The tetrahydrofuran was then removed from the filtrate by vacuum and the final product was vacuum distilled from the remaining filtrate. This resulted in a yield of 8.0 g (64% of theoretical) of (Me3Si)2NCH2CH(OMe)2.