Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:15]([C:22]1[S:26][N:25]=[C:24]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])[CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(Cc2ccccc2)sn1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(Cc2ccccc2)sn1

Procedure:
The 5-Benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isothiazole-3-carboxamide is prepared following method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride, 5-benzylisothiazole-3-carboxylic acid (which can be prepared by procedures known to the skilled in the art), HATU and N,N-diisopropylethylamine in DMF.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.I[CH2:22][CH3:23]>CC(C)=O>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([S:19][CH2:22][CH3:23])=[NH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CCI
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(N)=S)cc23)CC1
Solvent: CC(C)=O
Product: CCSC(=N)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 25.1 %

Procedure:
A solution of compound 65 (0.2 g, 0.698 mmol) in acetone (10 mL) was treated with iodoethane (0.33 mL, 4.189 mmol) at room temperature and the resulting solution was refluxed for 4 h. The reaction was brought to room temperature, and solvent was evaporated. The crude was diluted with sat. NaHCO3 solution (20 mL) and compound was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Evaporation of solvent and purification of crude by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 66 (0.055 g, 25%) as a solid. mp 77-79° C.; 1H NMR (DMSO-d6) δ 1.20-1.30 (m, 3H), 2.28 (s, 3H), 2.50-2.57 (m, 4H), 2.90-2.96 (m, 2H), 3.02-3.06 (m, 2H), 5.98-6.04 (m, 2H), 6.60-6.63 (m, 1H), 7.17-7.35 (m, 4H), 10.90 (s, 1H); ESI-MS m/z (%):: 315 (M+, 66), 311 (78), 249 (100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:17][CH:16]([CH2:18][NH:19][C:20](=O)[CH3:21])[O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH2:17][CH:16]([CH2:18][NH:19][C:20](=[S:32])[CH3:21])[O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Solvent: C1COCCO1
Product: CC(=S)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
(-)-5-Acetamidomethyl-3-(3-fluoro-4-(pyrrol-1-yl)phenyll)isoxazoline (Example 12) (452 mg) is combined with Lawesson's Reagent (655 mg) in 5 ml dioxane in a 25 ml one neck round bottom flask under nitrogen. The reaction is warmed to reflux for 30 minutes and is cooled to room temperature. The insoluble material is removed by filtration and the filtrate is concentrated in vacuo to an amber syrup. The crude material is chromatographed two times over 25 g silica gel (230-400 mesh), eluting with 3% methanol/dichloromethane while collecting 5 ml fractions. Fractions 10-30 are combined and concentrated to provide 345 mg of the title compound as an off-white solid, mp 152-153° C., [α]25D -27 (c 0.60, ethanol).
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10]2)=[O:4].[OH-].[K+].Cl>O.CN(C=O)C>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10]2)([OH:4])=[O:2]
Reactant: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCC(=O)O)ccc2c1
Yield: 77.9 %

Procedure:
2.3 g of methyl 6-methoxycarbonylmethoxy-2-naphthoate and 2.3 g of KOH are heated under reflux for 3 h in 100 ml of water and 10 ml of DMF. The mixture is then acidified to pH 0.3 using hydrochloric acid, and the precipitate which is deposited is filtered off with suction at RT. 1.7 g of methyl 6-carboxymethoxy-2-naphthoate are obtained;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
6-Chloro-3-nitropyridin-2-amine (0.8 g, 4.64 mmol) was added to a solution of (R)-ethyl piperidine-3-carboxylate (1.0 g, 5.16 mmol) and triethylamine (1.56 g, 15.48 mmol) in acetonitrile (20 mL) at room temperature. The reaction mixture was stirred at 80° C. for 3 h. The mixture was partitioned between ethyl acetate and water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 10-50% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.0 g). MS (ES+) (M+H) 295.22.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:25]([O-])=O)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([C:4]([CH:13]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:14][C:15]1[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:25])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1
Yield: 110.5 %

Procedure:
α-(2-Propenyl)-[2-(2-nitro-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (15.42 g; 31.12 mmole) was dissolved in methanol (110 ml) under argon at room temperature. Powdered stannous chloride dihydrate (36.52 g; 161.8 mmol; 5.2 eq.) was added followed by concentrated hydrochloric acid (50 ml) with stirring. After ~1.5 hours, Celite, ethyl acetate, and saturated potassium carbonate solution were added with stirring (the potassium carbonate solution was added portionwise). The suspension was filtered, and the solid rinsed with ethyl acetate (three times). The filtrate was concentrated, and the residue was washed with 10% methanol/water. The washings were concentrated and dried in vacuo giving ~16 g of a yellow oil. The solids (tin salts, Celite, potassium bicarbonate, etc.) that had been filtered from the reaction mixture were triturated in acetone (several times) and suction filtered through a pad of Celite. The acetone filtrate was concentrated, and the remaining residue was partitioned between chloroform and water. The chloroform layer was dried (magnesium sulfate) and concentrated, leaving 9.06 g of the title compound as a solid. The remaining product was assumed to be in the aforementioned ~16 g of yellow oil. The yellow oil was used "as is" in the next step, as was the 9.06 g of solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:21]([N:18]1[CH2:19][CH2:20][CH:15]([N:3]([CH3:2])[C:4]([C:6]2[CH:14]=[CH:13][C:9]3=[N:10][O:11][N:12]=[C:8]3[CH:7]=2)=[O:5])[CH2:16][CH2:17]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 1 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.58 g, 1.9 mmol) was suspended in chloroform (50 ml), and acetic anhydride (2 ml) and triethylamine (4 ml), were added. After stirring for 1 h, the mixture was washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (2×100 ml) and the combined organics dried (MgSO4) and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform/methanol (50:45:5) to give a white solid after crystallization from ethyl acetate/MTBE/hexane (470 mg). Mp=173-175° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.0 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.0 Hz, 1H); 4.90-4.70 and 4.05-3.80 (m, 5H); 2.89 (sb, 3H); 2.13 (sb, 3H), 1.95-1.60 ppm (m, 4H).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:35](Br)[C:36]#[CH:37]>C(#N)C>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:37][C:36]#[CH:35])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Temperature: 20 °C
Reaction time: 40 h

Procedure:
A suspension of 2.45 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate, 2.1 g of potassium carbonate, 0.95 g of potassium iodide, and 0.6 cm3 of propargyl bromide in 50 cm3 of acetonitrile was stirred for 40 hours at a temperature in the region of 20° C. in an inert atmosphere. After filtering the reaction mass, the filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography on a column of silica gel (particle size 20-45 μm; diameter 2.5 cm; mass 50 g), elution was carried out with ethyl acetate, and 60-cm3 fractions were collected. Fractions 6 to 12 were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 1.35 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate were obtained in the form of a gum.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:5][C:4]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccnc2ccccc12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc2c1CCCC2
Yield: 92 %

Procedure:
Using the general method of F. W. Vierhapper and E. L. Eliel (J. Org. Chem., 1975, 40, 2729), a solution of 4.97 g (34.7 mmol) of lepidine in 35 mL of trifluoroacetic acid was shaken with 580 mg of platinum oxide under 50 psi of hydrogen for 18 h. After filtering off the catalyst, the solution was concentrated to about 20 mL and diluted with 25 mL of water. The aquous solution was chilled in ice, and basified carefully with 35 mL of 50% aqueous sodium hydroxide. The aqeuous layer was then extracted with 4×50 mL of diethyl ether. The organic layers were dried over potassium hydroxide, decanted, and concentrated to yield 4.7 g (92% yield) of 4-methyl-5,6,7,8-tetrahydroquinoline as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[NH:14][C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:14]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:13](=[O:15])[C:12]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(CCCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl (3R)-3-(3,5-difluorophenyl)-3-methyl-5-oxo-1,4-diazaspiro[5.5]undecane-1-carboxylate from Step H (60 mg, 0.152 mmol) in THF (0.5 mL) at 0° C. was added NaH (12 mg of a 60% dispersion in oil, 0.30 mmol). After 5 min, ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was allowed to warm to ambient temperature and stirring was continued for 1 h. Saturated aqueous NaHCO3 (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 60:40, to give the title compound. MS: m/z=425 (M−C4H7).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:5][C:6]=1[CH:7]1[CH2:12][CH:11]=[N:10][C:9]([Cl:13])=[N:8]1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[N:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[N:8]=1
Reactant: FC(F)(F)c1ccc(-c2nc(Br)c(C3CC=NC(Cl)=N3)o2)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2nc(Br)c(-c3ccnc(Cl)n3)o2)cc1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
Synthesis of 4-bromo-5-(2-chloropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole: A solution of lithium diisopropylamide (1.8 M in THF-heptane-ethylbenzene, 1.4 mL, 2.6 mmol) was added dropwise into a cooled solution of 5-bromo-2-(4-(trifluoromethyl)phenyl)oxazole (620 mg, 2.1 mmol) in dry THF (20 mL) at −78° C. After 2.5 h, 2-chloropyrimidine (292 mg, 2.6 mmol) was added. After 10 min, the reaction flask was raised half way out of the acetone-dry ice bath and maintained for 30 min, after which the reaction was warmed to 10° C. in an ice-water bath and maintained for 1 h. The reaction was quenched with water (1 mL) and concentrated. The resulting mixture was partitioned between EtOAc (70 mL) and water (40 mL), and the layers were separated. The organic phase was washed with water, brine, dried (Na2SO4), and concentrated to give 859 mg of a residue as 4-bromo-5-(2-chloro-4,5-dihydropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole which was used in the next step without further purification: LCMS (m/z): 407.9 (MH+), tR=0.83 min. A suspension of 4-bromo-5-(2-chloro-4,5-dihydropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole (859 mg, 2.12 mmol) and MnO2 (1.8 g, 21.2 mmol) in EtOAc (10 mL) was irradiated at 110° C. for 10 min in a microwave reactor. The reaction was allowed to cool to rt and was filtered through a plastic membrane. The filtrate was concentrated and resulting residue was triturated with EtOAc to afford 234 mg of 4-bromo-5-(2-chloropyrimidin-4-yl)-2-(4-(trifluoromethyl)phenyl)oxazole: LCMS (m/z): 406.0 (MH+), tR=1.19 min.
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[CH2:19]([O:23][C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(NCCc1ccccc1)c1cccnc1F
Reactant: CCCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCCOc1ncccc1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
2-Fluoro-N-phenethyl-nicotinamide (196 mg, 0.802 mmol), n-butanol (700 μL, 7.65 mmol) and potassium bis(trimethylsilyl)amide (2.5 mL, 0.5 M in toluene) were combined and stirred for 5 minutes at room temperature. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a colorless oil (207 mg, 0.694 mmol, 86.5%). ESI-MS m/z calc. 298.2, found 299.2 (M+1)+. Retention time of 3.46 minutes. H NMR (400 MHz, CD3CN) δ, 0.95 (t, J=7.4 Hz, 3H), 1.34-1.44 (m, 2H), 1.63-1.70 (m, 2H), 2.91 (t, J=7.0 Hz, 2H), 3.65-3.73 (m, 2H), 4.41 (t, J=6.7 Hz, 2H), 7.08 (dd, J=7.5, 4.8 Hz, 1H), 7.23-7.37 (m, 5H), 8.01 (s, 1H), 8.25 (dd, J=4.8, 2.0 Hz, 1H), 8.39 (dd, J=7.5, 2.0 Hz, 1H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:14]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH2:20]([O:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)CCOCCCCC(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)CCOCCCC=Cc1ccc2c(c1)OCO2

Procedure:
0.07 g (0.37 millimol) of p-toluenesulphonic acid-monohydrate are added to 2.2g (0.0075 mol) of 1-(1-hydroxy-5-isopentyloxy-pentyl)-3,4-methylenedioxybenzene, dissolved in 150 cc of benzene. The solution is rapidly heated to boiling temperature and boiled at reflux over the course of 20 minutes and using a DeanStark-trap. After cooling, the benzene solution is extracted with saturated sodium bicarbonate solution, subsequently with water and saturated sodium chloride solution and dried with sodium sulphate. The solution is evaporated and the residue chromatographed on silica gel with hexane/ethyl acetate (97:3), whereupon the 1-(5-isopentyloxy-1-pentenyl)-3,4-methylenedioxybenzene is obtained as a pure, colourless oil. nD20 = 1.5248
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C([Mg]Cl)(C)C.C(OCC)C.[O:23]1[CH2:26][C:25](=[O:27])[CH2:24]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:25]2([OH:27])[CH2:26][O:23][CH2:24]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: O=C1COC1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cc(Cl)nc(C(F)(F)F)c2)COC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (1.00 g, 3.25 mmol, European Journal of Organic Chemistry, (18), 3793-3798, 2004) in tetrahydrofuran (20 mL) at 0° C. was added dropwise 2.0 M isopropylmagnesium chloride in diethyl ether (1.95 mL, 3.90 mmol, Aldrich). After stirring for 30 minutes at 0° C., a solution of oxetan-3-one (0.281 g, 3.90 mmol, Synthonix) in Tetrahydrofuran (5 mL) was added. After stirring for 1 hour, the reaction was quenched by the addition of water and ammonium chloride. The product was extracted with two portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes on a 40 g silica gel cartridge afforded purified product (0.31 g, 38%). LCMS (M+H)+: 254.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([OH:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:6]=2[CH:30]=1.[OH-].[Na+:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O-:21])=[O:20])[O:8][C@H:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:6]=2[CH:30]=1.[Na+:32]
Reactant: COc1ccccc1[C@H]1O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1[C@H]1O[C@H](CC(=O)[O-])C(=O)N(CC(C)(C)C)c2ccc(Cl)cc21

Procedure:
To a suspension of (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (12 g) in methanol (200 ml) was added 1N aqueous sodium hydroxide (27.7 ml). After the acid was dissolved completely, the mixture was concentrated in vacuo. To the residue was added ethyl acetate (200 ml) and the mixture was concentrated in vacuo. The deposited crystals were collected to give sodium (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (11.8 g) as colorless crystals (mp >300° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][C:6]=1[NH:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16])=O.[OH-].[NH4+:21]>C(O)C>[CH3:18][N:17]([CH3:19])[C:15](=[O:16])[NH:14][C:6]1[S:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH3:13])[C:5]=1[C:3]([NH2:21])=[O:2]
Reactant: CCCOc1csc(NC(=O)N(C)C)c1C(=O)OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1csc(NC(=O)N(C)C)c1C(N)=O
Temperature: 40 °C
Yield: 51 %

Procedure:
A solution of 2-(3,3-Dimethyl-ureido)-4-propoxy-thiophene-3-carboxylic acid methyl ester ( ) in ethanol (6 mL) was treated with concentrated ammonium hydroxide (6 mL) in a sealed tube and heated to 40° C. for 5 hours. The mixture was then cooled, evaporated, acidified with a small amount of acetic acid and purified via radial chromatography on a 2 mm plate using hexanes/ethyl acetate (3/1) plus 2% methanol as eluent to afford a white solid (15 mg, 55.3 micromol, 51%) 1H NMR (CDCL3, 400 MHz) 1.03 (t, 3H, J=7.3 Hz), 1.81-1.88 (m, 2H), 3.04 (s, 6H), 3.97 (t, 2H, J=6.6 Hz), 5.33 (broad s, 1H), 5.55 (s, 1H), 7.50 (broad s, 1H), 12.00 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:22][CH2:21][C:17]([CH2:23][OH:24])([CH2:18][CH:19]3Br)[CH2:16][O:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1(C)C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]34[CH2:22][CH2:21][C:17]([CH2:23][OH:24])([CH2:18][CH2:19]3)[CH2:16][O:15]4)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(C34CCC(CO)(CO3)CC4Br)cc2)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccc(C34CCC(CO)(CC3)CO4)cc2)nc1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
To a stirred solution of (1-(4-(5-aminopyridin-2-yl)phenyl)-6-bromo-2-oxabicyclo[2.2.2]octan-4-yl)methanol (240 mg, 0.617 mmol) in toluene (8 ml) and tetrahydrofuran (8 ml) at 40° C. in a microwave vial under nitrogen, was added the mixture of AIBN (40.5 mg, 0.247 mmol) and Bu3SnH (0.980 ml, 3.70 mmol) in toluene at 40° C. The reaction mixture was heated at 100° C. for 3 hours. Most of solvent was removed by evaporation under vacuum, and the residue was purified by chromotography (heptanes/acetone 1/2) to afford (1-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol (60 mg, 31%) as yellow solid. LC/MS, [MS+1] 311.1, RT: 0.80; (Condition E).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1.C[N+]1([O-])CC[O:15]CC1>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH:8]=[O:15])=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)c(CBr)cn1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-bromo-5-(bromomethyl)-2-chloropyridine (490 mg, 1.72 mmol), powdered 4 Å molecular sieves, and NMO (2.19 g, 18.74 mmol) then diluted with ACN (17 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C6H4BrClNO 219.9 (M+H+); Found: 220.0 (M+H+).