Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].N1CCCCC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:11]([C:10]#[N:14])[C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc(Br)c1
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: N#CC(C#N)=Cc1cccc(Br)c1

Procedure:
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malononitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile. Epoxide formation proceeds readily with commercial bleach at a pH of 5 to 6. Treatment with hydrobromic acid in methanol then affords the required methyl 2-bromo-2-(3-bromophenyl)acetate. Similarly prepared was methyl 2-bromo-2-(3-cyanophenyl)acetate
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26](S(C)(=O)=O)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:33]#[N:34].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:33]#[N:34])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: [C-]#N
Reactant: C[C@@H]1CN2c3c(cc4c(S(C)(=O)=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN2c3c(cc4c(C#N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 85 °C

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-8-(methylsulfonyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Example 182, 1.0 g, 2.15 mmol) in DMF was added KCN (700 mg, 10.75 mmol) followed by 18-crown-6 (catalytic) and the mixture was heated at 85° C. for 12 hours. The reaction mixture was cooled to room temperature and precipitated with diethyl ether (repeated twice to remove complete DMF). The precipitate was dissolved in EtOAc (50 mL) and washed with water (2×10 mL), dried over anhydrous sodium sulfate and, filtered, concentrated. The residue was purified by ‘combiflash instrument’ to give product as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(CO)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
2.0 g of 2-(4-chlorophenyl)-3-methylbutanol in 10 ml of a 20% mixture of dimethylformamide and toluene was added over a 5 minute period to sodium hydride (0.8 g, 50% in oil) in 20 ml of toluene at 110°-120° C, and the mixture was stirred for 15 minutes. 3.0 g of 3-phenoxybenzyl bromide in 15 ml of toluene was then added over a 15 minute period and the mixture was gently refluxed for 2 hours, then was cooled and 10 ml of mineral spirits was added. The mixture was poured into ice/hydrochloric acid, extracted with ether, washed with sodium bicarbonate solution and dried (MgSO4). The solvent was removed to give an orange oil, which was chromatographed on silica gel using 1:1 methylene dichloride:hexane as eluent to give 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16](=[O:27])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16]([O:27][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[N:15]1)[CH3:13]
Reactant: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1-c1cccc(C#N)c1
Temperature: 80 °C
Yield: 40.5 %

Procedure:
1,4-difluoro-2-nitrobenzene (0.63 mL, 5.9 mmol, 2.5 equiv) was added to a mixture of 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (500 mg, 2.3 mmol, 1 equiv) and potassium carbonate (970 mg, 7.0 mmol, 3.0 equiv) in dimethyl sulfoxide (5.9 mL). The reaction mixture was heated to 80° C. for 20 minutes, then cooled to 22° C. The crude reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-[1-ethyl-3-(4-fluoro-2-nitrophenoxy)-1H-pyrazol-5-yl]benzonitrile as light-yellow solid (328 mg, 40%). Calcd (M+1)+: 353.1. Found: 353.0.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(N(CC)CC)C.[CH3:30][S:31]([Cl:34])(=[O:33])=[O:32]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:34].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzothiophene-2-carboxamide hydrochloride are dissolved in 2 ml of DMF, 6.5 mg (0.05 mmol) of N,N-dimethyl-4-aminopyridine, 59.6 μl (0.43 mmol) of triethylamine and 16.61 (0.21 mmol) of methanesulfonyl chloride are added and the mixture is stirred at room temperature for 16 h. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of 1N aqueous hydrochloric acid and acetonitrile, then reconcentrated and dried under high vacuum. 15 mg (33.8% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=O)([O-:3])=[O:2].C(OC1(O[Si](C)(C)C)CC1)C.[N+]([C:29]1[CH:30]=[C:31]([CH:38]2[O:42]C(=O)C[CH2:39]2)C=CC=1[N+]([O-])=O)([O-])=O.[Cl:44]CCl>[Ti](Cl)(Cl)(Cl)Cl>[CH2:30]([CH2:31][C:38](=[O:42])[CH2:39][CH:7]([Cl:44])[C:6]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:29]
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: ClCCl
Reactant: O=C1CCC(c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCOC1(O[Si](C)(C)C)CC1
Product: CCCC(=O)CC(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
3,4-Dinitrobenzaldehyde (634.5 mg, 3.24 mmol.) was taken into dichloromethane (20 mL) and the resulting solution was cooled to 0° C. under a nitrogen atmosphere. [(1-Ethoxycyclopropyl)oxy]trimethylsilane (0.85 mL, 4.21 mmol.) was added by syringe followed by addition of titanium tetrachloride (0.4 mL, 3.56 mmol.) and the resulting mixture was allowed to slowly warm to room temperature over 12 hours then stirred an additional 3 days. The solution was partitioned with water and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration followed by purification of the residue using silica gel flash chromatography (1:1 to 3:1 ethyl acetate:hexane eluent) gave a less polar fraction ethyl 4-chloro-4-(3,4-dinitrophenyl)butanone (379 mg, 37% yield) as an amorphous residue and 5-(3,4-dinitrophenyl)dihydrofuran-2(3H)-one as a more polar fraction (338 mg, 41% yield). 1H NMR (400 MHz, CDCl3): 7.98 (d, 1H), 7.96 (d, 1H), 7.80 (dd, 1H), 5.11 (dd, 1H), 4.15 (q, 2H), 2.66-2.50 (m, 2H), 2.42-2.28 (m, 2H), 1.27 (tr, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCOc1ccccc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A 500 mL of round-bottom flask was charged with 2-bromophenol (43 g, 0.25 mol), 1-bromo-3-methylbutane (41 mL, 0.325 mol), acetonitrile (200 mL) and potassium carbonate (52 g). The reaction mixture was heated to 80° C. with stirring overnight. The reaction was cooled and filtered, and washed with acetonitrile. The filtrate was concentrated in vacuo. Vacuum distillation of the residue yielded 1-bromo-2-(isopentyloxy)benzene (83-86° C., 56 g, 93% yield).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CCC([O-])(C)C.[K+].C1(C)C=CC=CC=1.[NH:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.Cl[CH2:39][N:40]1[CH2:44][CH:43]([CH2:45][CH2:46][CH3:47])[CH2:42][C:41]1=[O:48]>CCOCC>[CH2:45]([CH:43]1[CH2:44][N:40]([CH2:39][N:33]2[CH:37]=[CH:36][CH:35]=[CH:34]2)[C:41](=[O:48])[CH2:42]1)[CH2:46][CH3:47]
Reactant: c1cc[nH]c1
Reactant: CCCC1CC(=O)N(CCl)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cn2cccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.8 %

Procedure:
18-Crown-6 (0.158 g, 0.2 eq, 0.6 mmol) is dissolved in absolute ether (20 ml). A 1.7 M solution of potassium tert-amylate in toluene (1.93 ml, 1.1 eq, 3.28 mmol) is added dropwise in a flow of argon. The reaction mixture is stirred for 15 min at room temperature. Pyrrole (0.2 g, 1 eq, 2.98 mmol) is added. The reaction mixture is cooled to −15° C., and a solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.603 g, 1.15 eq, 3.43 mmol) in absolute ether (5 ml) is added dropwise. The resulting solution is stirred for 16 h at 20° C. The contents of the flask are partitioned between 10 ml of water and 30 ml of ethyl acetate. The organic layer is separated. The aqueous one is subjected to additional extraction with ethyl acetate (2×20 ml). The combined extracts are dried with anhydrous Na2SO4 and evaporated. Purification by chromatography on silicagel (dichloromethane/acetone) afford 0.091 g of 4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a 100 mL round bottom flask under inert atmosphere was placed 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine (0.736 g, 2.54 mmol), 10% palladium on carbon (90 mg), ethanol (40 mL), and acetic acid (20 mL). The atmosphere was exchanged with hydrogen gas via balloon. The reaction was allowed to stir 3 days at room temperature, then filtered through celite and concentrated under reduced pressure to afford the crude as an orange oil. The crude mixture was purified via silica column chromatography with a solvent solution of 90%/10%/1% ratio of CH2Cl2/CH3OH/NH4OH, to afford the title compound. MS m/z=260 [M+H]+; Calc'd for C12H16F3N3: 259.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1.[CH3:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:18][N:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=[C:13]1[CH:11]1[CH2:12][N:9]([C:4]2[CH:3]=[C:2]([C:29]3[C:24]([CH3:23])=[N:25][CH:26]=[CH:27][CH:28]=3)[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:10]1
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Reactant: Cc1ncccc1B(O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2C)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of Intermediate 3 (0.015 g, 0.048 mmol), (2-methylpyridin-3-yl)boronic acid (9.9 mg, 0.072 mmol), and cesium carbonate (1 M, 0.12 mL, 0.12 mmol) in THF (0.5 mL) under an atmosphere of nitrogen was treated with bis(tri-tert-butylphosphine)palladium(0) (1.5 mg, 0.0029 mmol) and heated to 100° C. overnight. The mixture was cooled, stirred with Quadrapure for 3 h, filtered, and concentrated. The residue was purified by reverse phase HPLC to give Example 80. 1H NMR: (400 MHz, d6-DMSO) δ 8.68 (d, J=1.2 Hz, 1H), 7.91 (d, J=15.0 Hz, 1H), 7.68-7.63 (m, 2H), 7.51-7.48 (m, 1H), 7.35-7.27 (m, 2H), 6.83 (s, 1H), 4.79-4.74 (m, 2H), 4.65-4.56 (m, 3H), 3.80 (s, 3H), 2.56 (s, 3H), 2.53 (s, 3H). MS: m/z=371.4 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccncc1C
Reactant: CCCCc1ccc(CCCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2ccc(C)c(C)c2)cc1
Product: [Br-]
Yield: 79 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of 3,4-lutidine (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no lutidine left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (79%). 1HNMR (300 MHz, CDCl3, ppm), 9.20 (s, 1H), 9.03 (d, J=6.3, 1H), 7.72 (d, J=6.3, 1H), 7.00-7.07 (m, 4H), 4.87 (t, J=7.5, 2H), 2.60 (t, J=7.8, 2H), 2.54 (t, J=7.8, 2H), 2.49 (s, 3H), 2.46 (s, 3H), 1.99-2.04 (m, 2H), 1.50-1.66 (m, 4H), 1.28-1.36 (m, 2H), 0.90 (t, J=7.5, 3H). 13CNMR 157.60, 143.56, 141.92, 140.78, 138.40, 128.63, 128.57, 128.47, 61.00, 35.54, 34.98, 34.04, 31.59, 27.96, 22.73, 20.66, 17.36, 14.31.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:25](=[O:27])[CH3:26])[CH:12]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1ccc2cc(O)ccc2c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(6-hydroxy-2-naphthyl)carbamic acid ethyl ester (1 g, 4.32 mmol) and triethylamine (1.80 mL, 13 mmol) in dichloromethane (20 mL) at room temperature, is added acetyl chloride (0.369 mL, 5.19 mmol) dropwise. After stirring at room temperature for 3 hours, the reaction mixture is concentrated and purified by flash chromatography on silica gel (2:1 hexane/EtOAc) to give N-(6-acetyloxy-2-naphthyl)carbamic acid ethyl ester as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:11])=[O:10])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[CH:7]=2)[CH2:2]1)=[O:18]
Reactant: NC(=O)c1cccc(OC2CNC2)c1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2cccc(C(N)=O)c2)C1
Reaction time: 1 h

Procedure:
To a stirring solution of 7.0 g. (0.036 mole) of 3-(3-azetidinyloxy)benzamide in 75 ml. of dry benzene was slowly added 2.0 g. (0.036 mole) of methylisocyanate. Stirring was continued at room temperature for one hour. The solid which separated was filtered and recrystallized from 60% ethanol. The product weighed 6.0 g. (67%) and melted at 238°-240° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[N:24][CH:23]=2)[N:18]=1)=[O:29]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NCc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Br)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 2-bromobenzylamine hydrochloride (80.7 mg, 95%, 0.345 mmol) in anhy. DMF (5 ml) was added triethylamine (51.8 ul. 0.345 mmol). After 5 min, 2-[1,6]naphthyridinecarboxylic acid (40 mg, 0.229 mmol), 1-hydroxybenzotriazole hydrate (34.2 mg, 0.253 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (48.5 mg, 0.253 mmol) was sequentially added. The resulting mixture was allowed to stir at room temperature for 4 h and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aq. NaHCO3, dried over anhy. MgSO4, and concentrated to give the crude mixture Chromatography of the crude (Hex:EtOAc=1:1, pure EtOAc) afforded desired product as white solid (70 mg, 89% 129-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]1)=[O:7].N1(CCN)CCC[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:14][CH2:22][CH2:13][CH2:12]1)=[O:7]
Reactant: NCCN1CCCC1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 1.06 g, 9.28 mmol), as a brown solid (2.3 g, 85%)
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]2=[O:13])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1>ClCCl>[Br:12][C:11]1[C:10]2[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:1][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])(=[O:25])=[O:24]
Reactant: CC1(C)CCc2ccc(N)c(Br)c2C1=O
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CCc2ccc(NS(=O)(=O)c3ccccc3F)c(Br)c2C1=O
Yield: 84.5 %

Procedure:
A mixture of Example 362B (730 mg, 2.72 mmol) and 2-fluorobenzenesulfonyl chloride (0.396 mL, 2.99 mmol) in pyridine (2.20 mL, 27.2 mmol) and dichloromethane (10 mL) was reacted as described in Example 275C to yield 0.98 g of the desired compound. MS (ESI(−)) m/e 425 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.63-7.72 (m, 2H), 7.41 (t, 1H), 7.26-7.35 (m, 3H), 2.93 (t, 2H), 1.86 (t, 2H), 1.08 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[N:27]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:31]4[C:26]([O:25][CH3:24])=[N:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)c(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)n1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 2,6-dimethoxy-pyridin-3-ol (Aagile Labs Division of Tyger Scientific, Ewing, N.J., USA; 30 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water to give 4-[4-(2,6-dimethoxy-pyridin-3-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 29%) as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.96-2.04 (m, 2H), 2.18-2.30 (m, 2H), 2.90-3.05 (m, 2H), 3.90 (s, 3H), 3.95 (s, 3H), 4.25-4.38 (m, 2H), 4.90-5.00 (m, 1H), 6.37 (d, 1H, J=8.2 Hz), 7.41 (d, 1H, J=8.2 Hz), 8.03 (s, 1H), 8.50 (s, 1H). Mass spectrum MH+=457. HRMS Calcd. For C22H29N6O5 (MH+): 457.2194. Found: 457.2193.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[N:9]1([C:14](=C)[C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][N:11]=[N:10]1>>[CH3:6][N:4]([CH3:5])[CH:3]=[C:14]([N:9]1[CH:13]=[CH:12][N:11]=[N:10]1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(C(=O)OC)n1ccnn1
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)n1ccnn1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
522 g of dimethylformamide dimethyl acetal were added to 400 g of methyl 2-(1H-1,2,3-triazol-1-yl)acrylate, and the mixture was heated to the boil. Low-boiling components formed were distilled off. After 4 h, the mixture was cooled to 55° C., and 1050 ml of methyl tert-butyl ether/2-propanol (3:1 v/v) were metered in. The resulting suspension was cooled to 22° C. and filtered. The filter cake was repeatedly washed with methyl tert-butyl ether and dried under reduced pressure at 40° C. This gave 493 g of the title compound as a solid.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[Cl:42][C:43]1[CH:52]=[CH:51][C:46]([CH:47]=[CH:48][CH2:49]Cl)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:52]=[CH:51][C:46]([CH:47]=[CH:48][CH2:49][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:45][CH:44]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 51.1 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride were reacted to yield the title compound as a pale yellow crystalline powder (yield: 51.1%).