Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]1[C:39](B(O)O)=[CH:38][CH:37]=[N:36]1.O1CCOCC1>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.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:14]3)=[C:2]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:7]=1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Reactant: Cn1nccc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 6 %

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (80 mg, 0.166 mmol), potassium carbonate (115 mg, 0.832 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (84 mg, 0.666 mmol), tetrakis(triphenylphosphine)palladium(0) (19.23 mg, 0.017 mmol), dioxane (1109 μl) and water (555 μl). The reaction was heated in a microwave at 100° C. for 30 min. The resulting mixture was concentrated and purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were dried under a vacuum to provide a white solid 5-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (5 mg, 0.01 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.48 (s, 3H) 7.01 (s, 1H) 7.05 (d, J=1.82 Hz, 1H) 7.11 (s, 1H) 7.21 (s, 1H) 7.43 (d, J=6.41 Hz, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.53-7.64 (m, 3H) 7.64-7.75 (m, 3H) 8.11 (d, J=8.23 Hz, 1H) 8.34 (s, 1H) 8.43 (d, J=1.60 Hz, 1H); m/z (ESI) 482.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+].Cl>CO.[Cl-].[Zn+2].[Cl-]>[CH3:23][N:24]([CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:6]=[CH:7][CH:8]=1)[CH3:25]
Reactant: CNC
Reactant: O=Cc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CN(C)Cc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1
Reaction time: 0.5 h

Procedure:
The aldehyde compound 15 (346 mg, 1.19 mmol) in MeOH (40 mL) was treated with dimethyl amine (2M solution in MeOH, 7.16 mmol). The solution was cooled with an ice/water bath and treated dropwise with a solution of sodium cyanoborohydride (82 mg, 1.31 mmol) and zinc chloride (89 mg, 0.66 mmol) in MeOH (10 mL). The resulting solution was adjusted to pH=6-7 with 2M methanolic HCl. After stirring for 30 min., the reaction was quenched with conc. HCl (0.2 mL) and the methanol was removed by evaporation. The residue was diluted with water (30 mL). The solution was adjusted to pH=10-11 with KOH (s) and extracted with CH2Cl2 (30 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was crystallized (CH2Cl2/MeOH/hexanes) to give 2-(3-(N,N-dimethylamino)methylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 332 mg (87%), as shiny yellow crystals. mp 222-225° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.20 (s, 6H), 3.06 (m, 2H), 3.40 (m, 2H), 3.50 (s, 2H), 7.21 (t, 1H, J=7.7 Hz), 7.41 (br d, 1H, J=7.4 Hz), 7.50 (m, 4H), 7.69 (d, 1H, J=7.1 Hz), 8.05 (br t, 1H), 11.56 (br s, 1H); HRMS (FAB, MH+) Calcd for C20H22N3O: 320.1763, Found: 320.1753; Anal. (C20H21N3O.0.25 H2O) C, H, N.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=1>C1COCC1>[CH3:28][O:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH2:17][N:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCS(=O)(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Thiomorpholine 1,1-dioxide (0.242 g, 1.788 mmol) and triethylamine (0.19 mL, 1.341 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 74, 0.22 g, 0.894 mmol) in THF (2.2 mL). The reaction mixture was stirred overnight at room temperature before being concentrated under reduced pressure and purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 90/10) to afford the title product as a white solid (242 mg, 90%). 1H NMR (500 MHz, CDCl3): δ 3.00-3.04 (m, 4H), 3.09-3.12 (m, 4H), 3.71 (s, 2H), 3.98 (s, 3H), 7.01 (m, 1H), 7.09 (m, 1H), 7.84 (d, J=8.2 Hz, 1H). LC (Method C)-MS (ESI, m/z) tR 2.03 min, 301 [(M+H+), 100%].
Reaction SMILES: [F:1][CH:2]([O:7][CH:8](F)[C:9]([F:12])(F)[F:10])[C:3]([F:6])([F:5])[F:4].[CH3:14][Li].[Li]>C(OCC)OCC>[C:9](=[C:8]([O:7][CH:2]([C:3]([F:6])([F:5])[F:4])[F:1])[CH3:14])([F:12])[F:10]
Reactant: FC(OC(F)C(F)(F)F)C(F)(F)F
Reactant: [Li]C
Agent: [Li]
Solvent: CCOCOCC
Product: CC(OC(F)C(F)(F)F)=C(F)F

Procedure:
Another reaction was performed under similar conditions using a 1:2 molar ratio of bis-(1,2,2,2-tetrafluoroethyl)ether (32.5 grams, 0.15 mols) and CH3Li (105 mL of 3.0 M solution of CH3Li in CH2(OC2H5)2, 0.32 mols of the base). 43.1 grams of a crude product liquid was collected. GC analysis demonstrated that the liquid contained 1.5% bis-olefin, 0.4% mono-olefin, 0.1% unreacted starting ether, 4.3% unknown by-product, 7.3% CF2═C(CH3)OCHFCF3 (major by-product discussed above) and 84.5% CH2(OC2H5)2. These reaction conditions demonstrate that doubling the amount of the lithium reagent produces more of the by-product CF2═C(CH3)OCHFCF3 at the expense of the desired mono-olefin.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (29) and N,N-diisopropylethylaamine in dry dichloromethane was added. Water was added and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate. The purification gave N-benzyloxyacrylamide (30).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:16]I>C(Cl)Cl>[I:16][C:13]1[CH:14]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=[CH:11][C:12]=1[OH:15]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: II
Solvent: ClCCl
Product: CCCCCCCCc1ccc(O)c(I)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A mixture of 4-octyl phenol (0.15 g, 0.73 mmol), CF3CO2Ag (0.25 g, 1 mmol) and I2 (0.185 g, 0.73 mmol) in CH2Cl2 (10 ml) was stirred for 0.5 h at 0° C., then for 0.5 h at room temperature. The solution was filtered through Celite bead and washed with CH2Cl2 (30 ml). The filtrates were evaporated to dryness to give the title compound (0.21 g, 87%) as fawn oil. 1H NMR (CDCl3) 7.32 (d, 1H, J=8.34 Hz); 7.28 (d, 1H, J=1.26 Hz); 6.98 (dd, 1H, 8.37, 1.71 Hz); 6.62 (s, 1H); 4.69 (t, 2H, J=5.88 Hz); 3.62-3.38 (m, 4H); 2.59 (t, 2H, J=7.29 Hz); 1.56-1.51 (m, 2H); 1.34-1.2 (m, 10H); 0.81 (t, 3H, J=6.48 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH2:10]([O:14][CH:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[O:17])[CH2:11][CH2:12][CH3:13]>C(O)CCC>[CH2:6]([O:5][C:1]([C:2]([CH:16]([OH:17])[CH:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])[O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH2:3])=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(C=O)OCCCC
Reactant: C=CC(=O)OCCCC
Solvent: CCCCO
Product: C=C(C(=O)OCCCC)C(O)C(OCCCC)OCCCC

Procedure:
0.4 moles butyl acrylate and 70 g (0.355 mole) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1 to form 2-butoxycarbonyl-4,4-dibutoxy-3-hydroxy-1-butene as a colourless liquid which distilled at 130° C. under 0.2 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: BrCc1cccnc1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3cccnc3)c2c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.00 g, 3.86 mmol) in DMF (50 ml) was added NaH (463 mg, 19.3 mmol) and and 3-(bromomethyl)pyridine (2.62 g, 15.4 mmol). The reaction was stirred at 60° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→70% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[N+]=[N-])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N=[N+]=[N-])c2)COC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(N)c2)COC1

Procedure:
A solution of [5-(3-azido-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (497 mg, 1.50 mmol) in EtOAc (37 ml) was hydrogenated using Lindlar catalyst (10 h, room temperature). The mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure yielding the title compound in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 9.57 (br, 1H), 6.97 (br, 1H), 6.55 (s, 1H), 6.52 (d, 1H), 6.45 (br, 1H), 5.08 (br, 2H), 4.40-4.30 (m, 2H), 3.75-3.45 (m, 2H), 1.47 (s, 3H), 1.39 (s, 9H); MS: 306 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]2[CH3:35])=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(F)cc2)nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-8-(4-fluorophenyl)-9H-purine (48 mg, 0.1 mmol) in DMF (2 ml) was added potassium carbonate (28 mg, 0.2 mmol) and methyl iodide (6 μl, 0.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:50), yielding the pure title compound (40 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:14]=1)[N:11]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(Br)c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3ccncc3)c21
Temperature: 120 °C
Yield: 34.5 %

Procedure:
A mixture of 8-bromo-1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (89 mg, 0.19 mmol), 4-tributylstannanyl-pyridine (107 mg, 0.29 mmol) and PdCl2(PPh3)2 (27 mg, 0.039 mmol) in 4 mL of DMF was heated at 120° C. for 2.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound. MS: (+) m/z 458.43 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 27 %

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.88 g (0.017 mole), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone, 3.86 g (0.017 mole), and potassium carbonate, 5.53 g (0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g). The reaction mixture was filtered and stripped to dryness. The dark brown oil obtained was dissolvedin chloroform and extracted with 1N sulfuric acid and 5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed. This furnished a brown oil which was subjected to flash chromatography on silica gel using hexane-ethyl acetate for elution. A white solid was obtained by evaporating the fractions containing the product. The solid was extracted with diethyl ether and the mixture was placed in the freezer overnight. A white solid was obtained which was dried at 80° C. in vacuo overnight. A yield of 2.2 g (27%) of white crystalline solid, m.p. 129°-131° C. was obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=[C:31]5[NH:25][C:26](=[O:27])[NH:28][C:29]5=[O:30])=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cn4ccnc4)c3)nc12
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cn5ccnc5)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.233 mmol) in EtOH was added hydantoin (23 mg, 0.233 mmol) and piperidine (23 μL, 0.233 mmol). The mixture was heated at 70° C. for 48 hr and then purified by HPLC to yield 5-((5-(3-((1H-imidazol-1-yl)methyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=401)
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1.[NH4+].[Cl-]>C1COCC1>[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1
Reactant: COC1CC(C=O)C(OC)O1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1CC(C=C2SCCCS2)C(OC)O1
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
According to a procedure described in Boger, D. L.; Brotherton, C. E. J Org Chem. 1984, 49, 4050-4055, to a solution of 2-trimethylsilyl-1, 3-dithiane (1.2 mL, 6.3 mmol) in dry THF (40 mL) at 0° C. was added n-butyllithium (4 mL of 1.6 M in hexanes). After 15 minutes at 0° C. and 20 minutes at 4 mL of 1.6 M ambient temperature, a solution of 2, 5-dimethoxytetrahydrofuran-3-carboxaldehyde (1.00 g, 6.00 mmol) in dry THF (10 mL) was added dropwise. After 17 hours at ambient temperature, the resultant mixture was treated with saturated aqueous NH4Cl (10 mL) and partitioned between EtOAc and H2O. The layers were separated and the aqueousueous phase extracted with EtOAc:hex (1:1) two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford a residue which was purified via flash column chromatograpy with 10% EtOAc/hex as eluant to yield 1.06g (70%) of a mixture of diastereomeric 2-(2,5-dimethoxy-tetrahydrofuran-3-yl-methylidene)-1, 3-dithiane as a yellow oil, which was used without any further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]([CH:9](O)[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=1.[Br:15]C(C1C=CC=CN=1)CCC>>[Br:15][CH:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:8]=1)[CH2:10][CH3:11]
Reactant: CCCC(Br)c1ccccn1
Reactant: CCC(O)c1cccc(C(F)(F)F)n1
Product: CCC(Br)c1cccc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 1-(6-(trifluoromethyl)pyridin-2-yl)propan-1-ol (Example 238, Step A) following a procedure similar to the one described for the synthesis of 2-(1-bromobutyl)pyridine (Example 231, Step B). Mass Spectrum (ESI) m/z=268.0 (M+1) and 269.9 (M+1).
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)=[CH:10][CH:9]=2)CCCCC1.[Br:25]C1C=CC(C=O)=CC=1.C(O)CO>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:25][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1
Reactant: c1cc(P(C2CCCCC2)C2CCCCC2)ccc1C1OCCO1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
This is an example of synthesis of ligand 2. 2-(4′-Dicyclohexylphosphinophenyl)-1,3-dioxolane (Ligand 2): Part I. A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g). Part II. 2-(4′-bromophenyl)-1,3-dioxolane (1.0 g, 4.4 mmol) was dissolved in anhydrous diethyl ether (30 mL) and the solution was cooled to −78° C. t-Butyllithium (5.14 mL, 1.7 M solution in pentane, 8.8 mmol) was added dropwise with stirring. The reaction was stirred for 2 h at −78 ° C. Chlorodicyclohexylphosphine (1.13 g, 4.8 mmol) was added dropwise via a syringe at −78 ° C. with stirring. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 18 h. To the reaction mixture was added argon purged water (25 mL) slowly. The organic phase was separated under argon and the aqueous phase was washed with diethyl ether (20 mL). The combined organic phase was concentrated under vacuum to afford a colorless oil, which was crystallized from methanol to afford ligand 2 as a white crystalline solid having the structure shown below (yield: 1.4 g, 92%). 31P{1H} NMR (CDCl3): δ2.4.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ccccc3S(C)(=O)=O)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS(m/e): 443.3 (MH+).
Reaction SMILES: C1(C#C)C=CC=CC=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)#[CH:10].[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: C#Cc1ccccc1
Product: COc1ccc(-c2cn(-c3nc(C)c(C(=O)NCc4ccccc4)s3)nn2)cc1
Yield: 45 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 4-ethynylanisole to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 45% yield: mp 168-171° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.38-7.32 (m, 5H), 6.99 (d, J=8.8 Hz, 2H), 6.13 (br s, 1H), 4.63 (d, J=6.0 Hz, 2H), 3.86 (s, 3H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 160.2, 155.5, 153.3, 148.6, 137.4, 128.9, 127.9, 127.9, 127.4, 124.2, 121.8, 115.8, 114.4, 55.4, 44.4, 17.4; MS (ES+) m/z 406.30 (M+1).