Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[S:27])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:27])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3COC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3COC(C)(C)O3)CS[C@H]12)c1csc(N)n1
Yield: 66.2 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2,2-dimethyl-1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (58 mg) was reacted with iodomethyl pivalate (51 mg), followed by purifying the reaction product in the same manner as in Example 2, yielding the titled compound (45 mg; 66%) as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1nc(Br)ccc1OCc1ccccc1

Procedure:
6-Bromo-3-hydroxypyridine-2-carbonitrile (53.8 g) obtained in Reference Example 72(1) is dissolved in acetone (550 ml), and thereto are added benzyl bromide (35.6 ml) and potassium carbonate (43.1 g). The mixture is then heated under reflux for 4 hours. After allowing to cool, water (600 ml) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate once, and combined with the previous organic layer. The solution is washed with saturated brine and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1, followed by 3/1). The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (24.1 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:24][CH3:25]
Reactant: CCI
Reactant: COC(=O)c1cc(N2CCCCS2(=O)=O)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(N3CCCCS3(=O)=O)cc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-indole-6-carboxylate (D231) (180 mg, 0.58 mmol, 1 equiv) in DMF (3 ml) at room temperature was added NaH (60% dispersion in mineral oil, 24 mg, 0.6 mmol, 1 equiv) and the resulting mixture was stirred 15 min at this temperature. Ethyl iodide (64 μl, 0.8 mmol, 1.4 equiv) was added and the resulting solution was stirred for 1 h then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel gave methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-1H-indole-6-carboxylate (B147) (110 mg, 51%) as a yellow solid which was used in the next step without further purification. [M+H]+=337.0, RT=2.82 min.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:18])[CH2:12][NH:13][CH2:14][CH:15]([CH3:17])[CH3:16].[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[Br:19][CH2:20][C:21]([N:13]([CH2:12][C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:22]
Reactant: O=C(Br)CBr
Reactant: CC(C)CNCC(=O)N1CCc2ccccc2C1
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CBr
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a stirred solution of 1-(3,4-dihydro-1H-isoquinolin-2-yl)-2-isobutylamino-ethanone (0.45 g, 1.8 mmol) in THF (4.0 mL), a solution of bromoacetyl bromide (0.32 mL, 3.6 mmol) in 4.0 mL THF was added dropwise at −78° C., under argon. After 3 h (the temperature gradually rose to 10° C.) the reaction was concentrated and the remaining residue was diluted with methylene chloride and saturated NaHCO3. The layers were separated and the organic phase was washed with brine and then dried (MgSO4). Filtration and concentration gave the crude product which was purified via silica gel flash chromatography (0-5% MeOH/methylene chloride, 30 mL/min.) to give 0.34 g (51%) of 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:24]([CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[N:25]=[CH:26][C:10]=13)[CH2:2]2.C(=O)=O.[H][H]>O1CCCC1.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]3[N:24]([CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:31][CH2:32]4)[N:25]=[CH:26][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc([N+](=O)[O-])cc4)nc32)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1

Procedure:
A solution of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.13 g, 0.24 mmol) in tetrahydrofuran (5 mL) was degassed by the addition of crushed solid carbon dioxide. Palladium-on-carbon (5%, 20 mg) was then added. The mixture was stirred magnetically overnight under a balloon of hydrogen gas. The mixture was filtered through a pad of diatomaceous earth, eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to provide tert-butyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as a pale yellow foam. MS (ES+): 506.4 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2cccc(Br)c2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
7-Bromobenzo[d]thiazol-2-amine (550 mg, 2.40 mmol) and DMAP (330 mg, 2.70 mmol) were suspended in DCM (12 mL) and acetic anhydride (0.25 mL, 2.7 mmol) was added. The reaction was stirred under nitrogen at RT for 6 hours, the suspension was filtered, and the solid was washed with DCM. The solid was collected, and the filtrate was concentrated and treated with MeOH. This batch of solid was also collected by filtration. The filtrate was concentrated, and filtered through silica gel (40:1 DCM/MeOH) to provide additional products. The collected solids were combined to afford N-(7-bromobenzo[d]thiazol-2-yl)acetamide (433 mg, 67% yield) as a white solid. MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2S: 270 (79Br), 272 (81Br).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2C(F)(F)F)c1C#N
Temperature: 50 °C
Yield: 93.2 %

Procedure:
A reaction flask equipped with a cooling tube was loaded with 8.7 g of 3-nitrophthalonitrile, 9.4 g of 2-(trifluoromethyl)phenol, 13.8 g of anhydrous potassium carbonate and 350 ml of dimethyl sulfoxide, and the temperature was raised to 50° C. with stirring under nitrogen flow. After stirring at 50° C. for three hours, the heating was stopped. The reaction liquid was cooled and added into 500 ml of water, and the precipitated crystal was collected and dried to yield 13.5 g of the intended compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([C:32](=[O:33])[CH2:31][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])[N:3]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[C:2]2=[O:1])=[CH:35][CH:36]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(OCC(F)(F)F)cc(=O)[nH]c2=O)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)cc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethoxy)-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.33 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.071 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.59 g, 91%).
Reaction SMILES: [CH2:1](I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[Mg]Br>C1COCC1>[CH2:1]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ICc1ccccc1
Reactant: Br[Mg]c1cccs1
Solvent: C1CCOC1
Product: c1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.8 g (52 mmol) of NaI and 5 mL (43 mmol) of benzyl chloride in THF was heated at reflux for 2 h to form benzyl iodide in situ and then the reaction was cooled to rt. In a separate flask, 37 mg (0.87 mmol) of LiCl and 58 mg (0.43 mmol) of copper(II) chloride were dissolved in 5 mL of THF and stirred at rt for 5 min to form Li2CuCl4 in situ. The benzyl iodide reaction flask was fitted with an addition funnel and 3 mL (3 mmol) of a 1 M solution of 2-thienylmagnesium bromide in THF was added dropwise, followed by addition of the Li2CuCl4 solution, and then the remaining 2-thienylmagnesium bromide solution (49 mL, 49 mmol) was added at such a rate as to maintain the reaction temperature <40° C. and the reaction solution was stirred for 2 h at rt. The THF was removed in vacuo, and the residue was partitioned between 250 mL of Et2O and 150 mL of NH4Cl and separated. The organic layer was treated with 15 mL of piperidine and stirred for 18 h, then washed twice with 10% (w/v) aqueous HCl, filtered, concentrated and the dark red residue was purified by flash chromatography eluting with neat hexane to yield the title compound. GC-MS (M)+ 174.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:28](=[O:30])[CH3:29])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A flask was charged with tetrakis-(triphenylphosphine)-palladium (1.7 g, 1.48 mmol) under nitrogen. A solution of 6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (5.8 g, 18.55 mmol) in DMF (150 mL) was added. The flask was purged with nitrogen gas three times and tributyl-(1-ethoxy-vinyl)-stannane (6.59 ml, 19.47 mmol) was added. The temperature was increased to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, 20 ml of 3N HCl was added and the mixture was stirred for additional 2 hrs. Water was added and the product was then extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.8 g (yield: 79%) title compound as a dark yellow solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.31 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A): [MH]+=321, tR=5.07 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[CH:7]=1
Reactant: Cc1cncc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 46.9 %

Procedure:
A mixture of 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 4 (3.8 g, 9.5 mmol) and p-toluenesulfonic acid monohydrate (0.91 g, 4.8 mmol) in 150 mL of toluene was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a yellow solid (1.7 g, 47%): mp (DSC) 196-198° C.; Anal. Calc'd. for C17H14F3N3O2S: C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.50, H, 3.65, N, 10.82, S, 8.55.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.[CH3:12]C([O-])(C)C.[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([CH3:12])[N:6]=[CH:5]2
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc2[nH]ncc2cc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Br)c(F)cc21
Reaction time: 0.67 h
Yield: 43.7 %

Procedure:
To a solution of 5-bromo-6-fluoro-1H-indazole (4 g, 18.60 mmol) in DMF (20 mL) was added potassium 2-methylpropan-2-olate (2.087 g, 18.60 mmol). The resulting mixture was stirred for 40 min. CH3I (3.17 g, 22.32 mmol) was added dropwise. After stirring overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified with silica gel column chromatography with gradient hexanes:EtOAc to give 5-bromo-6-fluoro-1-methyl-1H-indazole (1.86 g, 42%) as light yellow solid.
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[N:3][OH:4].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[Cl:11])=[N:3][O:4][C:17]=1[CH3:18])=[O:19])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: ON=C(Cl)c1cnccc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Yield: 27.4 %

Procedure:
Combine chloro(4-chloro(3-pyridyl))(hydroxyimino)methane (2.40 g, 0.013 mol) with ethyl-2-butynoate (3.66 mL, 0.031 mol) in diethyl ether (150 mL) under a nitrogen atmosphere. Add triethylamine (2.27 mL, 0.016 mol) in a dropwise manner and stir over a weekend at ambient temperature. Quench the mixture with water and extract with ethyl acetate. Concentrate the combined extracts and elute over silica gel with methanol/dichloromethane to give the desired isoxazole (0.95 g, 27%) as an oil. ES(EI): M+ 266.0, 267.0, 268.0 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1C=CC=CC=1>CCO>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:6](=[O:14])[CH2:7][O:8][CH2:9][CH2:10][N:11]=[N+:12]=[N-:13])=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])[CH3:2]
Reactant: CCOC(=O)CC(=O)COCCN=[N+]=[N-]
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN=[N+]=[N-]
Temperature: 60 °C
Yield: 42.5 %

Procedure:
A mixture of 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (3 g, 13.94 mmol), 2-chlorobenzaldehyde (3 g, 21.34 mmol) and pyridine (1.5 mL, 1.47 g, 18.55 mmol) in EtOH (14 mL) was heated to 60° C. and maintained at this temperature for 3 h. The mixture was concentrated in vacuo. The concentrate was taken up in EtOAc (100 mL), washed successively with 1N HCl (25 mL) and brine (25 mL), dried (Na2SO4), filtered, concentrated in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 gram Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 2.00 g of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (mixture of E/Z isomers) and 1.01 g of recovered starting material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2cc(CNCCCN3CCN(CCCNCc4ccc5ccccc5c4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-naphtaldehyde (818 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 2-piperazin-1-yl-4-(trifluoromethyl)pyrimidine (250 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.1 mmol) and triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg, 1.2 mmol). After being stirred overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20%-40% EtOAc/hexanes) provided 290 mg of desired product. MS calculated for C23H34F3N5O3: (M+H) 486; found 386.1 (M-Boc+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH:18](C3C=CC=CC=3)[CH3:19])[CH:10]=2)=[CH:5][CH:4]=1.CO[C:28]1[CH:33]=[CH:32][C:31](C2CCCC(=O)C=2)=[CH:30][CH:29]=1.C1(CCCCN)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CC(=O)CCC2)cc1
Reactant: COc1ccc(C2=CC(NCCC(C)c3ccccc3)CCC2)cc1
Agent: NCCCCc1ccccc1
Product: COc1ccc(C2=CC(NCCCCc3ccccc3)CCC2)cc1

Procedure:
Following the general procedure of example 28, (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-(3-phenyl-butyl)-amine (2.8 g; 56% light yellow oil, MS: m/e=336.2 (M+H+)) was prepared from 3-(4-methoxy-phenyl)-cyclohex-2-enone (3.0 g; 14.8 mmol) and 4-phenyl-butylamine (2.21 g; 14.8 mmol).