Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH2:27][C@H:28]([N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[CH3:29])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:35]>>[CH3:34][N:30]([C@H:28]([CH3:29])[CH2:27][O:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:10]([CH3:35])[CH:11]=1)=[N:17][CH:18]=[N:19]2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1cscn1
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 13 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(1R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide (obtained as described in Example 93, preparation of starting materials) to give the title compound as a white solid in 13% yield; NMR spectrum (DMSO-d6 373K) 1.22 (d, 3H), 1.86 (s, 3H), 2.24 (s, 3H), 2.85 (s, 3H), 4.33 (m, 1H), 4.42 (t, 1H), 5.09 (m, 1H), 5.25 (s, 2H), 7.09 (d, 1H), 7.18 (d, 1H), 7.34 (d, 1H), 7.39 (s, 1H), 7.50 (d, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.08 (s, 1H), 9.51 (s, 1H); Mass spectrum MH+ 478.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)C>[N:15]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[C:5]=3[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc(Cl)sc12
Reactant: C1CCNCC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Cl)c2nc(N3CCCCC3)sc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Under a nitrogen atmosphere a solution of 1.7 grams (6.8 mmole) of 2,4-dichloro-7-nitrobenzothiazole in 150 mL of diethyl ether was stirred as 1.2 grams (13.7 mmole) of piperidine was added via syringe over a ten minute period. The reaction mixture, which had spontaneously warmed, was cooled with ice-water to ambient temperature, where it stirred for 40 minutes. The resulting precipitate was collected by filtration and washed with 50 mL of ethyl acetate. The filtrate was washed with aqueous 0.1N hydrochloric acid and two 50 mL portions of water. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a bright yellow-orange solid, which was combined with a material prepared by a similar route and purified by column chromatography on silica gel. Elution was accomplished with 7:1 followed by 5:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.3 grams of 2-(1-piperidinyl)-4-chloro-7-nitrobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=1.C(N(CC)CC)C>C(O)C.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>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[C:22]([F:28])[CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1F
Yield: 65.9 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.30 mmol), 4-bromo-2-fluorobenzaldehyde (48 mg, 0.24 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (51 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.00-7.97 (m, 2H), 7.46 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 7.25 (d, 1H), 2.62 (m, 1H), 1.95-1.77 (m, 4H), 1.58-1.56 (m, 4H), 1.46-1.44 (m, 2H). MS (ESI) m/z: Calculated: 322.27; Observed: 323.2 (M++1).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[C:6]1([C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:13][NH:14][C:15](=[O:21])[CH:16]([CH3:20])[CH2:17]CO)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:5][CH2:1][CH2:17][CH:16]([CH3:20])[C:15]([NH:14][N:13]=[C:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: BrC(Br)(Br)Br
Reactant: CC(CCO)C(=O)NN=C(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCBr)C(=O)NN=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 8.1 g (24.3 mmol) of carbon tetrabromide are added to a solution of 6.0 g (20.2 mmol) of N′-(diphenylmethylene)-4-hydroxy-2-methylbutane hydrazide and 6.3 g (24.3 mmol) of triphenylphosphane in 150 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 1 h and then concentrated and purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 2.7 g (37%) of the desired product; (log P(HCOOH): 3.76); 1H-NMR (ppm): δ (DMSO-d6)=1.12 (d, 3H), 1.79-1.86 (m, 1H), 2.33-2.38 (m, 1H), 2.62-2.67 (m, 1H), 4.10-4.14 (m, 1H), 4.25-4.29 (m, 1H), 7.29-7.65 (m, 10H); LC-MS: m/z=359 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[NH2:7])[CH:31]=[CH2:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: C=CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cc(F)ccc1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2-Amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (5.0 g, 22 mmol, 1 equiv.) was added to a solution of DIPEA (3.62 ml, 22 mmol, 1 equiv.) in THF (80 ml). The mixture was cooled to 0° C. and allyl chloroformate (2.36 ml, 22 mmol, 1 equiv.) in THF added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and trifluoroacetic acid (1:1) for 2 hours. The product was obtained after evaporation of the organic solvents.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 26 (287 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried and recrystallized by hexane and ether to yield 340 mg (90%) of white solids. M.P. 146° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.47 (s, 2H), 6.66 (t, J=2.5 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.29-7.33 (m, 3H), 7.44 (d, J=1.3, 8.7 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 475 (M+23). Anal. (C27H24N4O3) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:11][CH:12]([CH3:14])[O-:13].[CH3:15][CH:16]([CH3:18])[O-:17].[CH3:19][CH:20]([CH3:22])[O-:21].Cl[Ti+3:24]>CCOCC>[CH3:11][CH:12]([CH3:14])[O-:13].[CH3:15][CH:16]([CH3:18])[O-:17].[CH3:19][CH:20]([CH3:22])[O-:21].[CH3:1][C:2]1[CH:3]=[C:4]([Ti+3:24])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cl[Ti+3]
Reactant: Cc1cc(C)cc([Mg]Br)c1
Agent: CC(C)[O-]
Solvent: CCOCC
Product: Cc1cc(C)cc([Ti+3])c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mmoles of 3,5-dimethylphenylmagnesium bromide in 10 mL of ether was cooled to -78° C. under nitrogen and to this was added 10 mL of a 1M solution of chlorotitanium triisopropoxide. The solution was stirred at -78° C. for 30 minutes and used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:21]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(OCCN(C)C)nc1
Yield: 70.3 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[2-(dimethylamino)ethoxy]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (50 mg, 0.13 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.20 mmol) followed by formation of the dihydrochloride salt to afford the desired product (40 mg, 54%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.35 (br s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.28 (d, J=2.6 Hz, 1H), 7.76 (dd, J=8.8, 2.7 Hz, 1H), 7.35 (br s, 1H), 7.10 (br s, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.74-4.68 (m, 2H), 3.66-3.60 (m, 2H), 3.02 (s, 6H), 2.84 (s, 3H); ESI MS m/z 496 [M+H]+; HPLC 98.3% (AUC), tR=9.47 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][N:18]=[C:13]2[N:12]=1
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Yield: 92 %

Procedure:
25.5 g. of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one (0.1 mol.) are refluxed in 100 ml. of phosphorus oxychloride for 12 hours. After this time, the excess phosphorus oxychloride is distilled off in vacuo, the residue is treated with dry acetone and filtered off. 25 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidine are obtained, yield 92%; m.p. 196°-197°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:28](OC)([O:31]C)[O:29]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:28]([OH:31])[OH:29])[CH:3]=[C:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=2[O:9][CH2:8]1
Reactant: COB(OC)OC
Reactant: CC(C)(C)Cc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-(2,2-dimethyl-propyl)-2,3-dihydro-benzofuran (Intermediate 32, 0.7 g, 2.37 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 6 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].I[CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:14]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCI
Reactant: O=C(O)c1cccnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCSc1ncccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
After MeOH (20 mL) was added to 2-mercapto-nicotinic acid (1 g, 6 mmol), the mixture was cooled to 0° C., and 6 M NaOH aqueous solution (3.2 mL) was added slowly thereto. The reactant was stirred at 0° C. for 30 minutes. 1-Iodobutane (0.74 mL, 6 mmol) was added to the reactant, and the mixture was stirred under reflux at 80° C. for 16 hours. The reactant was concentrated under reduced pressure, and 6 M HCl aqueous solution was added thereto to adjust the pH of the solution to 7. The resulting precipitate was filtered and dried to obtain the title compound (1.27 g, 93%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][CH2:2][C:3]2([C:6]#[N:7])[CH2:5][CH2:4]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (1.0 g) in dichloromethane (15 ml) was added pyridine (4.1 ml) at 0° C., and the mixture was stirred at the same temperature for 15 min. To the obtained reaction mixture was added dropwise p-toluenesulfonyl chloride (3.9 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([Cl:17])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14]Cl)[C:6]=2[CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:27]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>CCCCCCC.CCOC(C)=O>[CH2:27]([CH:31]1[CH2:36][CH2:35][N:34]([CH2:14][CH2:13][CH2:12][N:7]2[C:6]3[CH:16]=[C:2]([Cl:1])[C:3]([CH3:18])=[C:4]([Cl:17])[C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]
Reactant: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3c2cc(Cl)c(C)c3Cl)CC1
Yield: 47.3 %

Procedure:
6,8-Dichloro-4-(3-chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225b), (2.44 g, 7.92 mmol), K2CO3 (2.19 g, 15.84 mmol), NaI (2.37 g, 15.84 mmol) and 4-butylpiperidine (1.172 g, 8.3 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2225F) (1.55 g, 47%). 1H NMR (CDCl3) δ 7.11 (s, 1H), 4.65 (s, 2H), 3.93 (t, 2H), 2.86, (d, 2H), 2.41 (s, 3H), 2.41 (s, 3H), 2.33 (t, 2H), 1.92-1.77 (m, 4H), 1.65 (d, 2H), 1.31-1.19 (m, 9H), 0.88 (t, 3H); 13C NMR (CDCl3) δ 163.5, 140.5, 129.9, 128.1, 123.7, 114.0, 67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.6, 29.2, 24.8, 23.1, 17.2, 14.2.
Reaction SMILES: [CH3:1][CH3:2].[F:3][C:4]([F:11])([F:10])[C:5]([F:9])=[C:6]([F:8])[F:7]>>[F:3][C:4]([F:11])([F:10])[CH:5]([F:9])[C:6]([F:8])([F:7])[CH2:1][CH3:2]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CC
Product: CCC(F)(F)C(F)C(F)(F)F

Procedure:
When a reaction between ethane and hexafluoropropene was carried out in a 250 ml. Hastalloy-lined autoclave at a temperature of 280° C and under an initial total pressure of 150 atmospheres, a similar yield (76% based on hexafluoropropene consumed) of 1,1,1,2,3,3-hexafluoropentane was obtained.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36])=O>>[CH3:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([CH3:2])[C:4]=1[CH:5]=[CH:30][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Cc1cccc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COC(=O)c1cccc(C=Cc2c(C)cccc2C)c1
Yield: 71 %

Procedure:
Coupling of (2,6-dimethylbenzyl)triphenylphosphonium bromide with methyl 3-formylbenzoate following the method described in Example 1 gave methyl 3-(2,6-dimethylstyryl)benzoate as a white solid 2.20 g (71%), isomer ratio 2:1 trans:cis.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:15][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and propylamine according to general procedure 1 providing the amino compound (247 mg, 100%) as a yellow solid: Rf=0.88 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=9.6 Hz, 1H), 7.49 (s, 1H), 6.41 (d, J=9.6 Hz, 1H), 4.47 (br, 1H), 3.41-3.37 (m, 2H), 1.70 (sext, J=7.3 Hz, 2H), 1.03 (t, J=7.5 Hz, 3H); ES-MS: (M+H)=255, 257 m/z.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=C([O-])[O-]
Reactant: OCc1c(F)cc(O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl iodide (0.13 mL, 2.08 mmol) was added dropwise to a solution of 3-chloro-5-fluoro-4-(hydroxymethyl)phenol (334 mg, 1.89 mmol) and potassium carbonate (287 mg, 2.08 mmol) in DMF (5 mL) and the reaction mixture stirred for 4 h at rt. The reaction mixture was partitioned between DCM and H2O, the organic layer separated and the aqueous further extracted with DCM. The combined organic phases were concentrated in vacuo to yield the title compound as a yellow oil (360 mg, 1.89 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[O-:18])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: ONC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C=[N+]([O-])C2CCCC2)cc1
Yield: 65.1 %

Procedure:
4-Ethoxybenzaldehyde (22.0 g, 0.1467 mol) and N-cyclopentylhydroxylamine (14.1 g, 0.1398 mol) were mixed into toluene (200 mL) with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol). The mixture was refluxed for 3 hrs under argon atmosphere with a Dean-Stark trap to remove generated water. The solution was rotary evaporated to give a residue which was purified by flash chromatography over silica gel with EtOAc as an eluant and then recrystallization from a mixed solvent of hexanes and EtOAc. The title compound was obtained as a solid (21.24 g 65.1% yield), m.p. 95.1° C. (Rf=0.18 on a silica gel plate using hexanes:EtOAc, 2:1, v/v, as an eluant).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][NH:12][CH3:13].[CH2:14]([O:21][C:22]([O:24]N1C(=O)CCC1=O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:22](=[O:24])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc([N+](=O)[O-])ccc1Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc([N+](=O)[O-])ccc1Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 1-(2-bromo-5-nitrophenyl)-N-methylmethanamine (7 g, 28.6 mmol, see WO 2008/079836 for preparation) in DMF (30 ml), was added N-(benzyloxycarbonyloxy) succinimide (8.54 g, 34.3 mmol) and N,N-diisopropylethylamine (9.98 ml, 57.1 mmol). The mixture was stirred rt for 1 h, then quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexane) to yield 36A (10.66 g, 28.1 mmol, 98% yield). MS (ESI) m/z: 379.2 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.92-8.02 (m, 2H) 7.74 (d, J=6.15 Hz, 1H) 7.33-7.42 (m, 2H) 7.28 (s, 3H) 5.22 (s, 1H) 5.15 (s, 1H) 4.61 (d, J=18.46 Hz, 2H) 3.02 (s, 3H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]Br>CN(C)C=O>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=c1[nH]c2ncccc2o1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C

Procedure:
0.01 mol of oxazolo[4,5-b]pyridin-2-one is dissolved in 100 ml of dimethylformamide. 0.011 mol of bromine is added via a dropping funnel. Stirring is maintained for 1 hour 30 minutes at room temperature and an ice/water mixture is added. The product is filtered off. It is washed with water. The product is dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.[Br:13]CC(C1C=C(Cl)C=CC=1Cl)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[O:12])[CH2:11][Br:13])[C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1cccc2c1OCO2
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Product: O=C(CBr)c1cccc2c1OCO2
Yield: 48 %

Procedure:
This compound was prepared from 1-benzo[1,3]dioxol-4-yl-ethanone (2.15 g, 13.1 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.54 g (48%) of 1-benzo[1,3]dioxol-4-yl-2-bromo-ethanone as an off-white solid.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:18]([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:35])=[O:5])[S:12][CH:13]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
2-[(4-{2-[Heptyl(4-nitrophenyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (200 mg) obtained in Example 303-3 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and hexane was added to the residue to give the title compound (108 mg) as a pale-yellow solid.