Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[N+:29]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])([O-:31])=[O:30]>>[N+:29]([C:32]1[CH:33]=[C:34]([NH:35][C:2]2([C:26]#[N:27])[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[CH:36]=[CH:37][CH:38]=1)([O-:31])=[O:30]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccc([N+](=O)[O-])c4)CC3)c(F)c2)C(=O)O1
Yield: 52 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 3-nitroaniline the compound was obtained in 52% yield.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([Cl:27])[C:23]([CH2:25]Cl)=[CH:24][C:18]=2[O:17]1.CCN(CC)CC>O1CCCC1>[Cl:27][C:22]1[C:23]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)=[CH:24][C:18]2[O:17][CH2:16][O:20][C:19]=2[CH:21]=1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: c1ccc(OCCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1cc2c(cc1CN1CCN(CCOc3ccccc3)CC1)OCO2
Temperature: 60 °C

Procedure:
1-[2-(phenoxy)-ethyl]piperazine (200 mg, 0.974 mmol), 6-chloropiperonyl chloride (200 mg, 0.974 mmol), and Et3N (415 μL, 3 mmol) were combined in tetrahydrofuran (THF 20 mL). The reaction mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated. The crude residue was chromatographed on silica (20% EtOAc/Hexanes) and the product fractions were collected and evaporated to an amber solid (186 mg, 51%). 1H NMR (CDCl3) δ: 2.5-2.7 (m, 8H), 2.8 (t, 2H), 3.5 (s, 2H), 4.1 (t, 2H), 5.9 (s, 2H), 6.81 (s, 1H), 6.9-6.94 (m, 3H), 6.96-6.98 (m, 1H), 7.26-7.3 (m, 1H). MS ELS+376. CHN: calc., 64.08, 6.18, 7.47; found, 63.87, 6.12, 7.44. mp: 72-76° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:9]=O>ClCCCl>[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1([CH2:2][CH:1]=[O:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=O
Solvent: ClCCCl
Product: O=CCc1ccccc1
Product: O=Cc1ccccc1
Temperature: 40 °C

Procedure:
1.98 millimoles styrene were added to a solution of 5.34 millimoles active oxygen in the form of the complex of hexamethyl phosphotriamide of oxodiperoxomolybdenum (MoO5 -HMPT) in 50 ml 1,2-dichloroethane, the mixture was then maintained at 40° C. for 4.5 hours whereupon the reaction products were anlysed by gas chromatography. 0.35 millimoles benzaldehyde and 0.08 millimoles alpha-tolualdehyde were obtained. The degree of conversion with respect to the olefin consumed was 43%. The results are given in table 1.
Reaction SMILES: COC([CH:5]1[C:12](=[O:13])[C:9]2([CH2:11][CH2:10]2)[C:8]2([CH2:15][CH2:14]2)[NH:7][C:6]1=[O:16])=O>C(#N)C.O>[CH2:11]1[C:9]2([C:12](=[O:13])[CH2:5][C:6](=[O:16])[NH:7][C:8]32[CH2:14][CH2:15]3)[CH2:10]1
Reactant: COC(=O)C1C(=O)NC2(CC2)C2(CC2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CC(=O)C2(CC2)C2(CC2)N1
Temperature: 25 °C

Procedure:
8,10-Dioxo-7-aza-dispiro[2.0.2.4]decane-9-carboxylic acid methyl ester (628 mg; 2.2 mmol) in acetonitrile/water (9 ml/0.9 ml) is refluxed for 50 minutes, cooled to room temperature, filtered and the filtrate evaporated to deliver the title compound as colorless solid (386 mg; 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[Br-:15].[CH2:16]([N:12]1[CH:13]=[CH:14][N+:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11]1)[CH2:17][CH3:18]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc([N+](=O)[O-])cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.3 mmol (1.00 g) 1-(4-nitrophenyl)imidazole and 6.3 mmol (0.780 g, 0.58 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 17 h to 90° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:7]1[CH:6]=[C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])[CH:10]=[CH:9][CH:8]=1
Reactant: NC(CO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1cccc(Cl)c1

Procedure:
The title compound was prepared with 2-amino-2-(3-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.48 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz, 3H), 7.21 (d, J=8.5 Hz, 2H), 6.83-6.72 (m, 3H), 6.67 (d, J=7.3 Hz, 4H), 6.39 (d, J=7.9 Hz, 1H), 5.09 (s, 1H), 3.14 (dd, J=10.7, 4.4 Hz, 1H), 2.93 (dd, J=10.7, 8.0 Hz, 1H); ESIMS m/z 518 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[C:18]1([NH:16][C:14]2[N:15]=[C:8]3[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:12][CH:11]=[CH:10][N:9]3[N:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N:24]1([C:21]2[CH:22]=[CH:23][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: Nc1nc2c(-c3cccnc3)cccn2n1
Product: c1ccc(Nc2nc3c(-c4cccnc4)cccn3n2)cc1
Product: c1cncc(-c2cccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)c1

Procedure:
(4-Morpholin-4-yl-phenyl)-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine and phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine were prepared from 8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (70.0 mg, 0.331 mmol) and 4-(4-bromo-phenyl)-morpholine (100.0 mg, 0.4130 mmol) in a manner analogous to Example 2d. (4-Morpholin-4-yl-phenyl)-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was isolated as a yellow solid (0.025 g, 20%). MP=226-228° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.16 (d, J=1.9 Hz, 1H), 8.66 (dd, J=4.8, 1.4 Hz, 1H), 8.46-8.41 (m, 2H), 7.61 (dd, J=7.4, 1.1 Hz, 1H), 7.54-7.49 (m, 2H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.00-6.93 (m, 3H), 6.69 (s, 1H), 3.90-3.86 (m, 4H), 3.14-3.09 (m, 4H). MS=373 (MH)+. Example 7, Phenyl-(8-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine, was a byproduct of the above reaction and was isolated as a yellow solid (0.007 g, 7%). MP=211-212° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.16 (d, J=2.1 Hz, 1H), 8.67 (dd, J=4.7, 1.4 Hz, 1H), 8.48 (d, J=6.8 Hz, 1H), 8.44 (ddd, J=7.8, 1.8, 1.8 Hz, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 7.39-7.34 (m, 2H), 7.04-6.98 (m, 2H), 6.87 (s, 1H). MS=288 (MH)+.
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[N+:19]([O-])=O)(=[O:5])[O:3][CH3:4].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]=1[NH2:19])(=[O:5])[O:3][CH3:4]
Reactant: COP(C)(=O)c1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COP(C)(=O)c1cc(Sc2ccccc2)ccc1N

Procedure:
To a mixture of methyl P-methyl-2-nitro-5-phenylthiophenylphosphinate (3.0 g) and ammonium chloride (5.3 g) in 40 ml of ethanol and 20 ml of water is heated to 70°, and iron (3.0 g) is added portionwise over a period of about 10 minutes. After the reaction is completed, the reaction mixture is filtered and the filtrate is concentrated to a small volume, followed by extraction with methylene chloride, drying and evaporation to give methyl P-methyl-2-amino-5-phenylthiophenylphosphinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[O-]S(C(F)(F)[F:19])(=O)=O.ClC1C=[N+](F)C=C(Cl)C=1.C(OCC)(=O)C>ClCC(Cl)(Cl)Cl>[F:19][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1
Agent: ClCC(Cl)(Cl)Cl
Agent: F[n+]1cc(Cl)cc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is added 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120° C. for 5 hours. Additional 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 0.25 g) is added and heating is continued for 1 hour. The solution is then cooled to room temperature and passed over a column of silica gel (hexanes followed by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.[CH:14]1([C:17]#[CH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:18]#[C:17][CH:14]2[CH2:16][CH2:15]2)[CH:7]=1
Reactant: C#CC1CC1
Reactant: COc1cc(Br)cn2ncc(I)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Br)cn2ncc(C#CC3CC3)c12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (50.0 mg, 0.142 mmol), cyclopropyl acetylene (0.018 ml, 0.212 mmol), tetrakis(triphenylphosphine)palladium (0) (16.4 mg, 0.014 mmol), and copper(I) iodide (4.1 mg, 0.02 mmol) were suspended in DMF (2 ml). Triethylamine (0.039 ml, 0.283 mmol) was added, the mixture was sparged with argon for 10 minutes, then heated to 60° C. overnight. LCMS analysis indicated incomplete reaction conversion. Cyclopropyl acetylene (0.018 ml, 0.212 mmol) was added and the mixture was stirred for 6 h, at which time, LCMS analysis indicated the reaction has proceeded further, but still conversion was still incomplete. Cyclopropyl acetylene (0.036 ml, 0.426 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford recovered 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (faster eluting) along with 6-bromo-3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridine (slower eluting).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:21]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:21][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1coc(=O)c2ccc(F)cc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Temperature: 80 °C

Procedure:
A mixture of methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g) and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid was heated at 80° C. for 16 h. The reaction was cooled to 40° C., diluted with 8 ml of water and the solid collected by filtration (1.38 g).
Reaction SMILES: C(=O)([O-])[O-].C[C:6]1([PH3+:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1.C[C:14]1([PH3+:20])C=CC=CC1.[Cl:21]([O-:25])(=[O:24])(=[O:23])=[O:22]>O>[C:6]1([PH2:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:21]([O-:25])(=[O:24])(=[O:23])=[O:22].[CH3:14][PH3+:20]
Reactant: CC1([PH3+])C=CC=CC1
Agent: O=C([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: C[PH3+]
Product: Pc1ccccc1

Procedure:
By following the same procedure as the 2nd step of Example 12 except that 10.0 g of 1-methylphenylphosphanium carbonate, 6.9 g of 60% perchlorate, and 10.0 g of water were used, 10.9 g (94.8% of the theoretical yield, yield of 67.6% to 1-phenylphosphane) of methylphosphanium perchlorate was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C)C=O>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous dimethylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5 N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3)δ4.1(m,2), δ3.68(S,3), δ3.03(dd,1,J=4.3,2.7 ), δ2.8(ABq,2), δ1.17(d,3,J=6.6), δ0.98(s,9), δ0.89(s,9), δ0.23(s,6), δ0.1(s,6).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-bromo-benzylamine (0.8 g, 2.807 mmol) in anhydrous DME (12 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol), pyridine-4-boronic acid (0.513 g, 4.211 mmol), and a 2M aqueous Na2CO3 solution (2.8 mL, 5.614 mmol). Heat the reaction overnight at 70° C. Cool the mixture to ambient temperature, dilute with EtOAc, and filter over Celite®. Wash the organic fraction with water, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give the title compound as an oil (0.295 g, 37%). GC-MS m/z: 284 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([C:27]([C:29]2[C:37]3[CH:36]=[N:35][CH:34]=[N:33][C:32]=3[N:31]([CH:38]([CH3:40])[CH3:39])[CH:30]=2)=[O:28])[CH:24]=[N:25][CH:26]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>N1C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:20][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([C:27]([C:29]3[C:37]4[CH:36]=[N:35][CH:34]=[N:33][C:32]=4[N:31]([CH:38]([CH3:40])[CH3:39])[CH:30]=3)=[O:28])[CH:22]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 50 °C
Yield: 49 %

Procedure:
To pyridine (4 mL) in a sealed vessel was added 2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid (67 mg, 0.24 mmol) (see Preparation 303), (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (52 mg, 0.18 mmol) (see Preparation 95) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (105 mg, 0.28 mmol). The reaction was heated at 50° C. for 18 hours and then evaporated in vacuo and purified by column chromatography (gradient of 100:0 to 88:12 DCM:MeOH) to give the title compound in 49% yield, 64 mg. LCMS (basic): Rt=0.81 min; m/z 549 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.Cl.Cl.N1CCNCC1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][Cl:22])=[CH:19][CH:18]=1>C(O)C>[Cl-:22].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:1]2[CH2:6][CH2:5][NH2+:4][CH2:3][CH2:2]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc(CN2CC[NH2+]CC2)cc1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 0.42 h
Yield: 91 %

Procedure:
A solution of 2.154 g(25 mM) of piperazine in 25 mL of absolute ethanol, was warmed in a bath at 65° C. Piperazine dihydrochloride hydrate (3.9765 g(25 mM)) was dissolved in the solution, by swirling. In the bath at 65° C. 3.6145 g(25 mM) of 4-fluorobenzyl chloride was added to the solution with vigorous stirring. The separation of white needles commenced almost immediately. After the solution had been stirred for an additional 25 minutes at 65° C., it was cooled, and the unstirred solution was kept in an ice bath for about 30 minutes. The crystals of piperazine dihydrochloride hydrate were collected by suction filtration, washed with three 5 mL portions of ice-cold absolute ethanol, and then dried. Approximately 3.989g(100.3%) of the dihydrochloride was recovered. Filtrate from this solution was evaporated to dryness at reduced pressure and crude 1-(4-methoxybenzyl)-4-piperazinium chloride was left as a residue. For removal of any piperazine dihydrochloride, the chloride may be crystallized after rapidly filtering a hot solution in about 20 mL of absolute ethanol. Concentration of the filtrate followed by cooling gave 5.248 g(91%) of 1-(4-fluorobenzyl)-4-piperazinium chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:36])([F:35])[CH:25](OS(C(F)(F)F)(=O)=O)[CH3:26]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:25]([CH3:26])[C:24]([F:36])([F:35])[F:23]
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)OC)c1
Temperature: 90 °C

Procedure:
To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester and the mixture was heated at 90° C. for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound. MS (m/e): 359.2 (M+NH4+, 80%), 342.0 (M+H+, 100%)
Reaction SMILES: OO.Cl[CH2:4][C:5]([C:7](Cl)(Cl)Cl)=[O:6].[CH:11]1[CH2:18][CH2:17]CCC[CH2:13][CH:12]=1.C(Cl)(Cl)Cl>O>[CH:4]12[O:6][CH:5]1[CH2:7][CH2:13][CH2:12][CH2:11][CH2:18][CH2:17]2
Reactant: O=C(CCl)C(Cl)(Cl)Cl
Reactant: C1=CCCCCCC1
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Product: C1CCCC2OC2CC1
Yield: 83 %

Procedure:
There were added 13.68 parts of a 50% aqueous hydrogen peroxide to a refluxing mixture of 3.92 parts of tetrachloroacetone, 11.58 parts of cyclooctene and 149 parts of chloroform. Water was removed continuously as it was formed, over a period of 4 hours of heating. The removed water was then added to the reaction mixture. The organic phase was then separated from the aqueous phase. Based on VPC analysis there was obtained an 83% yield of cyclooctene oxide.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[O:39]1[CH2:43][CH2:42][CH2:41][C@@H:40]1[CH2:44][NH2:45]>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:45][CH2:44][C@H:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NC[C@H]1CCCO1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (R)-(tetrahydrofuran-2-yl)methanamine (45.6 mg, 0.45 mmol) was added and the reaction mixture was stirred overnight at 85° C. The solvent was evaporated under reduced pressure and the crude crude was purified by flash column chromatography using dichloromethane and methanol as eluent and gave (R)-tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (75 mg, 33%). MS (ES+) m/z 506.4 (M+H)+