Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[CH3:2][NH+:3]([CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C.[O:28]1[CH2:47][CH:29]1[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>C(O)(C)C>[Cl-:1].[CH3:2][N+:3]([CH3:20])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:47][CH:29]([OH:28])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][Si:35]([CH3:46])([O:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[O:36][Si:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: C[Si](C)(C)O[Si](C)(CCCOCC1CO1)O[Si](C)(C)C
Reactant: CCCCCCCCCCCCCCCC[NH+](C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CC(O)COCCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 80 °C

Procedure:
A 500-ml, three-necked, round-bottomed flask was equipped with a stirrer, addition funnel, dry ice/acetone condenser, thermometer and electric heating mantle. The flask was flushed continuously with argon. The flask was charged with 167.2 g (0.55 equivalent) of dimethyl hexadecyl ammonium chloride (Sartomer Chemical Company, West Chester, Pa.), 0.028 g (0.27 milliequivalent) of triethylamine (Aldrich), and 250 g of isopropanol. To the stirred flask contents 65.2 g of the epoxy trisiloxane of Example 1 was added over a ten-minute period. The reaction mixture was stirred and heated at 80° C. for five hours to form a clear solution. The reaction mixture was cooled to ambient temperature and flushed overnight with dry argon. The solvent and other low-boiling materials were removed by rotary evaporation at 45° C. The yield of the quaternary ammonium salt (Compound II), a light yellow oil, was 118 g (87%). The elemental analysis was as follows:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]([C:34]1[C:39]([CH3:40])=[CH:38][C:37]([C:41](C)(C)[O:42][SiH2]C(C)(C)C)=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]([C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH2:41][OH:42])=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CO)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Tetrabutylammonium fluoride (25.1 g 79.6 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-methylpyridin (18.0 g, 39.8 mmol) in THF (150 mL). The reaction mixture was stirred overnight at room temperature. Concentration under reduced pressure followed by flash chromatography (hexane/EtOAc, 50:50) gave 2-[N,N -bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-3-methylpyridin (8.0 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:14]#[N:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[O:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:20]>O>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:14]([NH2:15])=[O:20])=[C:8]([C:10]([F:13])([F:11])[F:12])[O:9][C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(C(F)(F)F)oc2cc(O)ccc2c1=O
Solvent: O
Product: NC(=O)c1c(C(F)(F)F)oc2cc(O)ccc2c1=O

Procedure:
A mixture of 3 g of 7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-1-benzopyran-3-carbonitrile, 4 ml of conc. sulfuric acid and 1 ml of water was heated for 11/2 hours at an internal temperature of 120°-135°C. The clear dark solution was poured onto ice. The solid was filtered and recrystallized from methanol, mp > 310° C.
Reaction SMILES: [Br:1][CH:2]1[CH:11](Br)[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH3:18][OH:19]>>[Br:1][CH:2]1[CH:11]([O:19][CH3:18])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: O=C1c2ccccc2C(Br)C(Br)c2sccc21
Reactant: CO
Product: COC1c2sccc2C(=O)c2ccccc2C1Br

Procedure:
A suspension of 20 g of 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one in 400 cc of methanol is boiled at reflux for 5 hours. 9-Bromo-9,10-dihydro-10-methoxy-4H-benzo[ 4,5]cyclohepta[1,2-b]thiophen-4-one (M.P. 103°-106°) is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Br[CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: CCCSCCCBr
Reactant: N#Cc1ccc(CCCCNCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCSCCCN(CCO)CCCCc1ccc(C#N)cc1

Procedure:
5.0 g of 4-[4-[(2-hydroxyethyl)amino]butyl]benzonitrile and 4.9 g of 1-bromo-3-(propylthio)propane were dissolved in 50 ml of isopropanol. 6.3 g of potassium-carbonate was added and the mixture was refluxed over night and thereafter filtrated and evaporated. The oily residue was purified by column chromotography. Yield: 4.3 g of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Yield: 480.1 %

Procedure:
2-Piperazin-1-yl-ethanol (1.30 g, 1.0 mmol) and triethylamine (2.8 mL, 2 mmol) were dissolved in methylene chloride (20 mL). The solution was cooled to 0° C. and methanesulfonyl chloride (0.78 mL, 1 mmol) was added dropwise. The mixture was warmed to r.t., and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (1.0 g, 48%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][C:5]2=O.NC1C=CC(C)=CC=1.C(C(OCC)=O)#CC(OCC)=O.P(Cl)(Cl)([Cl:40])=O.CN(C)C1C=CC=CC=1>O.C1(C)C=CC=CC=1>[Cl:40][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=Nc2ccc(C)cc2C(=O)C1
Agent: CCOC(=O)C#CC(=O)OCC
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: Cc1ccc(N)cc1
Product: CCOC(=O)c1cc(Cl)c2cc(C)ccc2n1

Procedure:
Ethyl 6-methyl-4-quinolone-2-carboxylate (6.8 g, itself prepared from p-toluidine and diethyl acetylenedicarboxylate according to the general procedure outlined in J. Med. Chem., 1968, 11. 1218), phosphorus oxychloride (2.2 ml), N,N-dimethylaniline (7.46 ml) and toluene (80 ml) were heated together for 3 hours at 90° C. and cooled to laboratory temperature. The mixture was poured into a mixture of ice and water (100 ml) and extracted with chloroform (4×100 ml). The combined extracts were evaporated and the resulting oil was purified by chromatography on a silica gel column using a 1:4 v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) as eluent. There was thus obtained as an oil ethyl 4-chloro-6-methylquinoline-2-carboxylate (4.2 g). A mixture of a portion (3.5 g) of this product and ethanol (80 ml) was stirred at laboratory temperature and an aqueous N sodium hydroxide solution was added. After stirring for 2 hours the mixture was carefully acidified to pH 2 by adding aqueous 2N hydrochloric acid solution. The precipitated solid was filtered off, washed with water and with ether and dried to leave 4-chloro-6-methylquinoline-2-carboxylic acid as an off-white solid (2.65 g). A mixture of a portion (1 g) of this product and thionyl chloride (10 ml) was gently heated at 80° C. for 1.5 hours and the excess of thionyl chloride was evaporated. The residue was dissolved in dry acetonitrile (25 ml) and added dropwise to an aqueous solution of ammonia (specific gravity 0.880, 25 ml). After stirring at room temperature for 1 hour the white precipitate was filtered off, washed with water and dried in air to leave 4-chloro-6-methylquinoline-2-carboxamide as an off-white powder (0.8 g) which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[CH:25]=CC=[CH:22][CH:21]=1.[OH-].[K+]>CCO>[CH3:12][C:7]1[CH:6]=[C:5]([NH:4][C:1]2[CH:22]=[CH:21][CH:20]=[CH:25][CH:2]=2)[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: Brc1ccccc1
Reactant: CC(=O)Nc1cc(C)cc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)cc(Nc2ccccc2)c1
Temperature: 175 °C
Yield: 47.4 %

Procedure:
A mixture of 9.6 g (58.8 mmole) of N-acetyl-3,5-dimethylaniline, 8.13 g (58.8 mmole) of potassium carbonate (dried at 155° C. under vacuum), 23 g (147 mmole) of bromobenzene (dried over molecular sieves), and 1.12 g (5.9 mmole) of cuprous iodide was heated in a 175° C. oil bath under a reflux condenser under nitrogen for 18 hours. The mixture was cooled to room temperature and triturated with 1 liter of benzene. The solution was concentrated in vacuo. The residue was treated with 60 mL of EtOH and 7.76 g (118 mmole) of potassium hydroxide and the resulting mixture was heated to reflux for two hours. The mixture was cooled and the solvent removed in vacuo. The residue was taken up in 150 mL of hexanes and 20 mL of EtOAc and the resulting solution was washed with 2×100 mL of 2N aqueous HCl and 60 mL of water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 210 g of silica gel with 2 liters of 3:1 hexanes CH2Cl2 to give 5.5 g (47%) of a light red oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:33])([CH2:27][C:28](=O)[CH2:29][S:30][CH3:31])[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][CH3:31])=[C:28]2[CH2:27][C:22]([CH3:33])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSC
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CSc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(C(C)C)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio-4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 143°-144°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[C:4]([F:21])[CH:3]=2)=[CH:29][CH:28]=1)(=[O:25])=[O:26])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Ethylsulfonyl benzene boronic acid. MS (M+H) 445.2
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([CH3:15])[CH3:14]>O1CCOCC1>[CH:13]([O:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:15])[CH3:14]
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CC(C)Oc1cccc(N)c1
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-isopropoxyaniline (125 mg, 0.829 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid produced was isolated by filtration and then purified by preparative TLC (2% MeOH/DCM) to yield 5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=297)
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:14]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[C:12]([CH3:13])[N:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)NN=Cc1nc(Cc2ccccc2)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(Cc2ccccc2)n2c(=O)[nH]ncc12

Procedure:
A mixture of 4.89 gm. of 3-[(2-benzyl-5-methyl-4-imidazolyl)methylene]carbazic acid ethyl ester and 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 244°-247° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Brc1ccc2ccccc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ccccc3c2)CCN1c1cnccc1C1CC1
Yield: 11.5 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 70 mg, 0.344 mmol) was reacted with 2-bromonaphthalene (85.68 mg, 0.413 mmol), 1,4-dioxane (5 mL), copper iodide (6.5 mg, 0.034 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (4.8 mg, 0.034 mmol) and potassium phosphate (219 mg, 1.034 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 13 mg of the product (12% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)c(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-nitroaniline (4.33 g), benzenesulphonyl chloride (3.25 ml) and pyridine (2.5 ml) was stirred and heated to 100° C. for 18 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and 2M aqueous hydrochloric acid. The organic phase was washed with water, dried and evaporated. The residue was recrystallised from ethyl acetate to give N-(2-chloro-4-nitrophenyl)benzenesulphonamide (6.07 g), m.p. 155°-157° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[N+:9]([O-])[CH:10]=1)[CH3:3].CO.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:12][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(OC(C)C)c[n+]1[O-]
Solvent: CO
Product: CC(=O)OCc1ccc(OC(C)C)cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
5-(1-methylethoxy)-2-methylpyridine 1-oxide (234 mg, 1.40 mmol) was dissolved in acetic anhydride (3.0 mL), and the mixture was stirred at 140° C. for 1 hour. At room temperature, the reaction solution was added methanol, stirred, concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate) and [5-(1-methylethoxy)pyridin-2-yl]methyl acetate (209 mg (yield 71%)) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>O1CCCC1.O>[CH2:26]([O:25][C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)=[O:24])[CH3:27]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 635.3 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (5.00 g, 1.68 mmol) in tetrahydrofuran (150 ml) was added ethyl chloroformate (1.82 g, 16.8 mmol) and triethylamine (1.70 g, 16.8 mmol) and the mixture was stirred under reflux for 2 hr. After cooling, the reaction mixture was diluted with water, then extracted with ethyl acetate. The extracts were washed with 1N-HCl and water, dried, then evaporated under reduced pressure to a residue, which was chromatographed to afford 2-ethoxycarbonylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (3.954 g, 64% yield): NMR(CDCl3)δ 1.31(t, 3H), 1.60(t, 3H), 4.25(m, 3H), 6.58(s, 1H), 6.95-7.58(m, 8H) ppm; IR(nujol) 3280, 1720, 1290, 1230, 1080 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[C:30]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[CH3:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(CN(C)C(=O)/C=C/c2ccc(N)nc2)Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)CC2=C(C)c3ccccc3C2)cn1
Yield: 249 %

Procedure:
To a solution of (E)-3-[6-aminopyridin-3-yl]-N-methyl-N-(3-methyl-1H-inden-2-ylmethyl)acrylamide (0.159 g, 0.5 mmole), from Example 26, in anhydrous THF (20 mL) was added NaHCO3 (0.126 g, 1.5 mmole) followed by acetic anhydride (0.153 g, 0.15 mmole). The mixture was heated at reflux for 40 hr, then was concentrated under vacuum. The residue was partitioned between H2O and EtOAc, and the organic layer was dried over MgSO4, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound (0.135 g, 74.8%) as an off-white solid: MS (ES) m/e 362.2 (M+H)+. Anal. Calcd for C22H23N3O2.0.25 H2O: C, 72.20; H, 6.47; N, 11.47. Found: C, 72.42; H, 6.45; N, 11.07.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[CH:28]=[C:2]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:16][CH:17]=[N:18]1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(F)c1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(-c4cccnc4)ccc2OCC3)c(F)c1

Procedure:
5-(9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole was treated with 3-pyridineboronic acid pinacol ester using standard Suzuki condition to yield 408. NMR: (CDCl3): 3.15 (2H, t), 4.31 (2H, t), 6.82 (1H, s), 7.03-7.18 (3H, m), 7.32-7.38 (2H, m), 7.51-7.55 (1H, m), 7.72 (1H, s), 7.82 (1H, d), 8.05 (1H, s), 8.55 (1H, d), 8.80 (1H, s). MS. ESI+500 (MH++MeCN)
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[C:16]1([NH:22][C:23](=[S:26])[NH:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:25][NH:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[S:26])[C:6]2=[O:14]
Reactant: NNC(=S)Nc1ccccc1
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Agent: Cl
Solvent: O
Product: O=c1c(=NNC(=S)Nc2ccccc2)c(=O)c2cc(O)ccc12

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenyl thiosemicarbazide hydrochloride, reflux for 2 hours.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A suspension of 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (14.38 g, 57.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.08 g, 62.9 mmol) and Cs2CO3 (55.9 g, 171 mmol) in DMF (150 mL) was sparged with Ar, treated with Pd(PPh3)4 (6.60 g, 5.71 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to near-dryness. The residue was treated with EtOAc, washed with 5% LiCl (1×) and the aqueous layer back-extracted with EtOAc (4×). The combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (12.28 g, 72%). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=2.8 Hz, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.97 (dd, J=8.9, 2.8 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 6.97 (dd, J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.Br[C:10]([CH3:15])([CH3:14])[C:11](Br)=[O:12].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][CH:10]1[CH2:15][C:4]2[C:5](=[CH:6][C:1]([CH3:8])=[CH:2][C:3]=2[CH3:7])[C:11]1=[O:12]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
m-Xylene (34.1 g, 0.32 moles) and 2-bromoisobutyryl bromide (73.9 g, 0.32 moles) were stirred in methylene chloride (500 mL) at 0° C. as AlCl3 (108.98 g, 0.82 moles) was added slowly as a solid under a nitrogen flow over a 20 minute period of time. The reaction was then allowed to stir at 0° C. for 1 hour and then for 16 hours at 20° C. After the reaction period the mixture was poured on crushed ice and then filtered through diatomaceous earth (Celite™ brand). The mixture was then extracted with 1 M HCl (2×100 mL), 1 M NaHCO3 (1×100 mL), and H2O (1×100 mL) and the organic layer dried over MgSO4. Filtration followed by removal of the volatiles resulted in the isolation of a yellow oil. Vacuum distillation resulted in the isolation of the desired product as a pale yellow oil (50.4 g, 89.9 percent yield).