Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 2-bromo-6-fluorobenzaldehyde (Description 39; 10.0 g, 49.3 mmol) and (trimethylsilyl) acetylene (13.94 ml, 98.6 mmol) in anhydrous N,N-dimethylformamide (250 ml) under an atmosphere of nitrogen was added triethylamine (10.25 ml, 73.95 mmol), copper (I) iodide (0.94 g, 4.93 mmol) and Pd(PPh3)2Cl2 (1.73 g, 2.47 mmol). The mixture was degassed and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers were washed with water (3×300 ml), brine (200 ml) then dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% Et2O in iso-hexanes to give the title compound (10.38 g, 95%).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([OH:11])(=[S:10])[CH3:9].CS(O[CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:18]1)(=O)=O>O>[C:8]([S:10][CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[CH3:23])[CH2:18]1)(=[O:11])[CH3:9]
Reactant: CC(O)=S
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(C)=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To 300 ml of anhydrous N,N-dimethylformamide were added 7.35 g of sodium hydride in the form of a 55% w/w/ dispersion in oil, followed by 12.5 g of thioacetic acid. The mixture was then stirred for 10 minutes, with ice-cooling, after which 40 g of 3-methanesulphonyloxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were added. The mixture was then stirred for 3 hours at 65° C. After the reaction mixture had been allowed to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a column of silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give 30 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[NH:4][N:3]=1.[OH-].[K+].Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1)=[O:16]>CN(C)C=O.O>[CH3:1][C:2]1[N:3]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[CH2:21][CH2:22]2)=[O:16])[N:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[CH:6]=1
Reactant: N#CC1CCN(C(=O)CCl)CC1
Reactant: Cc1cc(C(F)(F)F)[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C#N)CC1
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-5-trifluoromethylpyrazole (9.3 g, 62 mmol) and 45% aqueous potassium hydroxide solution (7.79 g, 62 mmol) in N,N-dimethylformamide (25 mL) was cooled to 5° C., and 1-(2-chloroacetyl)-4-piperidinecarbonitrile (i.e. the product of Example 1, Step A or A1) (11.2 g, 60 mmol) was added. The reaction mixture was stirred for 8 h at 5-10° C., then diluted with water (100 mL), and filtered. The filter cake was washed with water and dried at 50° C. in a vacuum-oven to give 15 g of the title compound as a solid containing 3% of its regioisomer, i.e. 1-[2-[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinecarbonitrile.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]2[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]3[S:13][CH2:12][CH:11]([CH3:14])[O:10][C:9]=32)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:14][CH:11]1[O:10][C:9]2[C:15]3[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]=2[S:13][CH2:12]1)=[CH:4][CH:3]=[C:2]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=3
Reactant: CC1CSC2=C(O1)c1cc(Br)ccc1C(=O)C2=O
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CSC2=C(O1)c1cc(N3CCCCC3)ccc1C(=O)C2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 24.5 %

Procedure:
To a solution of 9-bromo-2-methyl-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.1 g, 0.31 mmol) in 1,4-dioxane (1.0 mL) was added piperidine (0.061 mL, 0.616 mmol) and potassium carbonate (0.043 g, 0.308 mmol). The reaction mixture was stirred at 90° C. for 18 hours. The resulting mixture was filtered and solvent was removed under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 50% EtOAc in hexanes) to give the product as a purple solid (0.025 g, 25%). M.p.=225-226° C.; 400 MHz 1H NMR (CDCl3) δ: 7.91 (d, J=8.8, 1H), 7.09 (d, J=2.8, 1H), 6.72 (m, 1H), 4.62 (m, 1H), 3.49 (m, 4H), 3.07 (d, J=13.6, 1H), 2.88 (m, 1H), 1.71 (br. s, 6H), 1.60 (d, J=6.4, 3H); LCMS: 330 [M+H].
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[C:8](Cl)(=[O:10])[CH3:9].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[CH:5][C:6]=1[Cl:7]
Reactant: Clc1ccsc1Br
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-3-chlorothiophene (10.7 g, 51.5 mmol) was dissolved in dichloromethane (73.5 ml). The flask was equipped with a desiccant filled drying tube and the solution was chilled in an ice bath. Acetyl chloride (6.06 g, 77 mmol) was added followed by addition of aluminum trichloride (8.24 g, 61.8 mmol) over about 2 minutes (reaction bubbled vigorously as aluminum trichloride was added). The reaction mixture was stirred overnight, allowing to warm to room temperature, and then added cautiously and with stirring to a 1-L beaker containing ˜200 mL sat sodium bicarbonate. The mixture was stirred for 30 minutes and diluted with dichloromethane (˜100 mL). The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate, water, and brine. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to give a crude solid. This material was recrystallized from hot hexanes to give the title compound.
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][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[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][CH2:25][O:26][C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1OCCCCl
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: N#Cc1ccccc1OCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 7.41 g (0.025 mole) of [4-[bis(4-fluorophenyl)methyl]piperidine, 4.90 g (0.025 mole) of 2-(3-chloropropoxy)benzonitrile, and potassium carbonate, 5.54 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was concentrated to dryness and the resulting residue was partitioned several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a brown oil. The oil was triturated with ethyl ether and placed in a freezer overnight. White crystals were obtained and dried in vacuo overnight at room temperature. A yield of 5.15 g (46.1%) of analytically pure material, m.p. 88.5°-90° C., was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and tributylphenylstannane: MS (m/z) 343.1 (M+1).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@@H:2]1O>O.C(O)(=O)C>[OH:10][C@@H:3]1[C@@H:4]([OH:9])[C@H:5]([OH:8])[C:6](=[O:7])[CH:1]=[CH:2]1
Reactant: O=C1C[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Yield: 48 %

Procedure:
0.05 g of 2-deoxy-scyllo-inosose synthesized according to the method described in WO 2006/112000 was added to 1 mL of 5 N acetic acid water, and the resulting mixture was heated at 100 degrees centigrade for 2 hours. After the completion of the reaction, a quantitative analysis was carried out using HPLC and as a result, (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one was obtained at a yield of 48%. At this time, 35% of the raw material of 2-deoxy-scyllo-inosose was collected.
Reaction SMILES: [N:1]([C@@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:2]=[N-:3].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:30][CH3:31]>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:29]([C:30]1[N:3]=[N:2][N:1]([C@@H:4]2[NH:7][C:6](=[O:8])[C@H:5]2[NH:9][C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:31]=1)=[O:32])[CH3:35]
Reactant: [N-]=[N+]=N[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn([C@@H]2NC(=O)[C@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 51.4 %

Procedure:
To a solution of 2.0 g of (3S,4S)-4-azido-3-tritylamino-2-azetidinone in 40 ml of toluene is added 1.33 g of ethyl propionate, and the mixture is refluxed for one hour and then cooled. The resulting crystalline is collected by filtration and dried to give 1.3 g of (3S,4S)-4-[4-(ethoxycarbonyl)-1,2,3-triazol-1-yl]-3-tritylamino-2-azetidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:30][OH:34])=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(CCNC(=O)Cc2ccc(Cl)cc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 62.4 %

Procedure:
2.25 g (5.49 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)acetamide and 2.39 g (13.73 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 90° C. for 1.5 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with 5% hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water and 5% hydrochloric acid were added to the residue, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 1.50 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])(=O)C.[K+].O>CN(C)C(=O)C.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>[F:10][C:9]([F:12])([F:11])[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:15][CH:14]=1)[C:18]1=[CH:19][C:20]3[C:25]([N:17]1[CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:13]
Reactant: O=C(NCc1ccc(Br)c(Cn2ccc3ccccc32)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NCc1ccc2c(c1)Cn1c-2cc2ccccc21)C(F)(F)F
Temperature: 130 °C

Procedure:
The product from step b) (716 mg, 1.74 mmol) and potassium acetate (177 mg, 1.80 mmol) were dissolved in N,N-dimethylacetamide (17 mL). The solution was deoxygenated in vacuo and put under nitrogen atmosphere prior to addition of tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol). The resulting suspension was heated on an oil bath at 130° C. for 3 h. Addition of water (100 mL) gave a white precipitate which was filtered, washed with water and dried to give the sub-title compound
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1cc(C)ccc1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)cc1C
Temperature: 0 °C
Reaction time: 7 h
Yield: 89 %

Procedure:
In a three-neck flask, 60 g (4.4×10−1 mol) of 2,5-dimethylanisole was dissolved in 600 ml of CHCl3, and then cooled to 0° C. using ice bath. To the solution, 70.32 g (4.4×10−1 mol) of Br2 in 200 ml of CCl4 was added dropwise over 1 hour. While maintaining the reaction solution at 0° C., the reaction was left to stand for 7 hours. The reaction solution was washed 3 times with NaOH saturated solution and distilled under reduced pressure, to remove the solvent. The remaining liquid was vacuum-distilled, to produce the title compound in a liquid state. Yield: 89% (83.14 g).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2].CCN(CC)CC.[O:22]=[C:23]1[NH:32][C:31]2[N:30]=[C:29]([O:33][CH2:34][CH2:35][CH2:36][CH:37]=O)[CH:28]=[CH:27][C:26]=2[CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:29]3[N:30]=[C:31]4[C:26]([CH2:25][CH2:24][C:23](=[O:22])[NH:32]4)=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(N2CCNCC2)n1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1
Reaction time: 0.08 h
Yield: 47.4 %

Procedure:
To a solution of 1-(6-ethyl-pyridin-2-yl)-piperazine (0.41 g, 2.13 mmol) in dichloroethane (15 mL) was added Et3N (0.22 g, 2.13 mmol) and the mixture was stirred for 5 min. 4-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.50 g, 2.13 mmol) was added as a solution in dichloroethane (3 mL) and the mixture was stirred at room temperature for 15 min. NaBH(OAc)3 (0.63 g, 3.00 mmol) was added as a solid and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by liquid chromatography (Biotage 40M, gradient elution 100% CH2Cl2 to 99% CH2Cl2/MeOH) afforded the title compound as a sticky white foam (413 mg, 1.01 mmol, 47%). The foam was dissolved in Et2O and treated with anhydrous HCl gas to give a white precipitate. The mixture was filtered and dried to give a white powder (287 mg). MS: APCI: M+1: 410.3 (Exact Mass: 409.25).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH:1]1([S:4]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCO
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CCCCOS(=O)(=O)C1CC1
Temperature: -10 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Cyclopropanesulfonyl chloride (5 g, 35 mmol, 1 eq) was dissolved in an excess BuOH (20 ml), the reaction mixture was cooled at −10° C. and pyridine (5.8 mL, 70 mmol, 2 eq) was slowly added dropwise. The mixture was slowly warmed at room temperature and stirred overnight. The solvent was removed under reduced pressure and the resulting white solid was dissolved in CHCl3. The organic phase was washed with water, brine and dried (MgSO4) and concentrated to give an oil (4.8 g, 24.9 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ 4.25 (t, 2H), 2.46 (m, 1H), 1.74 (m, 2H), 1.45 (m, 2H), 1.25 (dd, 2H), 1.09 (dd, 2H), 0.93 (t, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4]>O.[OH-].[Na+].C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.68 g (92.3 mmol) of sodium borohydride, dissolved in 30 ml of water to which 5 ml of 5N NaOH have been added, is added dropwise and with stirring to a solution of 13.86 g (92.3 mmol) of 4-formylbenzoic acid in 200 ml of absolute ethanol. The reaction medium is left thus for 5 hours with stirring at room temperature. The ethanol is then removed by evaporation under vacuum and the residue is taken up with water and then acidified with 5N hydrochloric acid: the precipitate obtained is separated by filtration on a sinter.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:43][OH:52])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 13) (288 mg, 0.79 mmol) and N,N-diisopropylethylamine (138 μl, 0.79 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (452 mg, 1.19 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (552 μl, 3.16 mmol) was then added, followed by the hydroxylamine hydrochloride (165 mg, 2.38 mmol) and the mixture stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue wasa partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as a foam (126 mg).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Anhydrous chromium trioxide (CrO3) (1.94 g, 19.4 mmol) is added to a solution of anhydrous pyridine (3.07 g, 38.8 mmole) in anhydrous methylene chloride (CH2Cl2) (50 ml). The resulting mixture is stirred at room temperature for 15 mins. A solution of N-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2-one (0.74 g, 3.23 mmol) in anhydrous CH2Cl2 (5 ml) is added all at once. After stirring at room temperature for 5 mins, the mixture is decanted and the dark, gummy residue is washed with more CH2Cl2. The combined CH2Cl2 supernatant is evaporated i.v. The residue is taken up in diethylether and filtered to remove chromium salts. The ethereal filtrate is washed with 5% NaHCO3, 5% HCl, 5% NaHCO3 and brine, dried with MgSO4, filtered, and evaporated i.v. to yield N-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.54 g) as an off-white solid: ir(CHCl3) 5.77, 5.80, 7.36, 7.60, 7.99, 8.50 and 11.95 cm-1 ; nmr (CDCl3) δ0.23(s, 3), 0.27 (s, 3), 0.98 (s, 9), 2.63 (ddd, 1), 2.65 (dd, 1), 3.07 (ddd, 1), 3.37 (dd), 3.97 (m, 1), and 9.78 (t, 1); mass spectrum m/e 170 and 128.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C(N1CCNCC1)CC1C=CC=CC=1.Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([O:33][CH3:34])=[C:28]([F:35])[CH:27]=1.[CH:36]1([CH2:42][CH2:43][CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([CH2:42][CH2:43][CH2:44][CH:45]2[CH2:46][CH2:47][N:48]([C:26]3[CH:27]=[C:28]([F:35])[C:29]([O:33][CH3:34])=[CH:30][C:31]=3[F:32])[CH2:49][CH2:50]2)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: C1CCC(CCCC2CCNCC2)CC1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: COc1cc(F)c(N2CCC(CCCC3CCCCC3)CC2)cc1F
Yield: 98.2 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-phenethylpiperazine were replaced with 4-bromo-2,5-difluoroanisole (338 mg) and 4-(3-cyclohexylpropyl)-piperidine (953 mg), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=3:1) to provide 4-(3-cyclohexylpropyl)-1-(2,5-difluoro-4-methoxyphenyl)piperidine (523 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]1[N:21]=[C:20]([CH3:22])[O:19][N:18]=1)[CH:11]=[CH:10]2.C[O:24][B:25](OC)[O:26]C.Cl>O1CCCC1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([B:25]([OH:26])[OH:24])[CH:16]=[CH:15]3)[N:21]=1
Reactant: COB(OC)OC
Reactant: Cc1nc(-c2ccc3cc(Br)ccc3c2)no1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3cc(B(O)O)ccc3c2)no1
Temperature: -78 °C

Procedure:
4.76 ml n-butyllithium solution (1.6 M in hexane) are added dropwise to 1.00 g 3-(6-bromo-naphthalen-2-yl)-5-methyl-[1,2,4]oxadiazole in 15 ml of tetrahydrofuran at −78° C. The reaction mixture is stirred for another hour at −78° C., then 1.94 ml trimethylborate are added dropwise. Then the reaction mixture is left to heat up to ambient temperature and stirred overnight at this temperature. Then 9 ml 1 N hydrochloric acid are added while cooling with an ice bath. After 10 minutes at ambient temperature the tetrahydrofuran is distilled off in vacuo using the rotary evaporator and the flask residue is extracted with ethyl acetate. The combined organic extracts are dried on magnesium sulphate and evaporated down. The crude product is stirred with diisopropylether, suction filtered and dried.