Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12]Br.[C:15]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][N:28]1[CH2:27][CH2:26][N:25]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:30][CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1cccc(C)c1NC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(C)c1NC(=O)CCN1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a mixture of N-(2,6-dimethylphenyl)-3-bromopropanamide (1 g, 4.5 mmol) and N-carbobenzyloxypiperazine (1,7 g, 6.8 mmol) in 10mL of acetone was added potassium carbonate (0.93 g, 6.8 mmol). The mixture was refluxed for 24 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was purified using column chromatography, to provide N-(2,6-dimethylphenyl)-3-(4-carbobenzyloxypiperazinyl)propanamide, a compound of formula (3). B. To N-(2,6dimethylphenyl)-3-(4carbobenzyloxypiperanzinyl)propanamide (1.3 g) in 10 mL of methanol was added 10% Pd/C, and the mixture was hydrogenated at 30 psi for 24 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure, to afford N-(2,6-dimethylphenyl)-3-piperazinylpropanamide, a compound of formula (4),which was used without further purification. C. A mixture of N-(2,6dimethylphenyl)-3-piperazinylpropanamide (0.15 g, 0.57 mmol) and 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole (0.127 g, 0.57 mmol) in 8 mL of ethanol was refluxed for 24 hours. The solvent was removed under reduced pressure, and the residue was purified using preparative TLC.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([C:35]3[CH:39]=[CH:38][S:37][C:36]=3[C:40]#[N:41])[CH:32]=[CH:33][CH:34]=2)O1>CN(C)C(=O)C.O.C(=O)([O-])O.[Na+]>[CH:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:33]3[CH:32]=[C:31]([C:35]4[CH:39]=[CH:38][S:37][C:36]=4[C:40]#[N:41])[CH:30]=[CH:29][CH:34]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1)=[O:12]
Reactant: O=Cc1ccn2c(Br)cnc2c1
Reactant: CC1(C)OB(c2cccc(-c3ccsc3C#N)c2)OC1(C)C
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1sccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Temperature: 80 °C
Yield: 67.7 %

Procedure:
3-Bromoimidazo[1,2-α]pyridine-7-carboxaldehyde (1.15 g, 5.16 mmol), potassium phosphate (2.19 g, 10.31 mmol) and 3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile (2.58 g, 8.26 mmol) were dissolved in N,N-dimethylacetamide (15 ml) and the mixture degassed with N2 for 15 min. Tetrakis(triphenylphosphine)pallidum(0) (0.30 g, 0.26 mmol) was added and the mixture heated at 80° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with water (20 ml) and saturated sodium hydrogencarbonate solution (20 ml), then extracted with ethyl acetate (2×75 ml). The combined organic fractions were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give a black oil. The oil was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%). The solid obtained was triturated with diethyl ether which gave the title compound (1.15 g, 68%) as a white powder. Oxalate salt, white powder. 1H NMR (360 MHz, d6-DMSO) δH 7.30 (1H, dd, J 7 and 1), 7.70-7.88 (4H, m), 8.08 (1H, s), 8.16-8.22 (2H, m), 8.44 (1H, s), 8.78 (1H, d, J 7), 10.05 (1H, s); m /z (ES+) 330 (M++H).
Reaction SMILES: C([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][CH2:15][CH:9]([NH2:8])[CH2:10][C:11]=2[CH:19]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CC(N)CCC2
Yield: 105.9 %

Procedure:
A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (1.0 g) and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5.5 hours. After filtration, the filtrate was evaporated in vacuo to give 3-methoxy-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (720 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1[C:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][C:8]=1[NH2:21].N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH:7]1[C:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][C:8]=1[NH:21][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Ethyl chloroformate (0.16 mL, 1.6 mmol) was added to a solution of 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) and pyridine (0.36 mL, 4.5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred overnight at room temperature. The crude material was diluted in ethyl acetate and washed with water, dried (MgSO4) and concentrated. The solid was washed with hexane to provide ethyl 7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylcarbamate (0.40 g). MS (ESI) m/z 274; Profiled 100% purity, m/z 274.1 ([M+H]+), 2.5 min, Anal. Calcd. for C16H,9NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.18; H, 6.95; N, 5.01.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([CH3:24])([CH3:23])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)=[O:8])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]([CH3:24])([CH3:23])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(C)(C)C(=O)c1ccc(O)cc1

Procedure:
The product from step 1 (1.25 g, 3.83 mmol) and 10% Pd/C (0.3 g) in MeOH (50 mL) was hydrogenated on a Parr apparatus until TLC indicated completion of the reaction. The mixture was filtered, concentrated to an oil and used directly in the next step; MS m/z 204 (M-OMe).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1.ClCCl>[F:24][C:25]1[CH:26]=[C:27]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1cccc(F)c1)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.7 %

Procedure:
To a stirred solution of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.0 g, 3.22 mmol, 1.0 eq.) in pyridine (5 mL) and dichloro methane (20 mL) at 0° C. was dropwise a solution of 3-fluorobenzene-1-sulfonyl chloride (940 mg, 4.83 mmol, 1.5 eq.) in dichloromethane (30 mL). The mixture was stirred at room temperature for 6 h. Thin layer chromatography and LC-MS showed reaction completed. The mixture was quenched with 50 mL water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to afford 1.987 g of methyl 2-(2-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (pyridine included) as light yellow solid, which was used in next step without further purification.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:30][C@H:31]([C:36]([NH:38][C@H:39]([C:43]([OH:45])=[O:44])[CH:40]([CH3:41])[CH3:42])=[O:37])[CH2:32][CH:33]([CH3:34])[CH3:35])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:46]([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH-:60])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)CCCCCCC[NH-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that discribed in Example 1, using as starting materials 81 mg of BOC-Phe-His-OH, 79 mg of H-Leu-Val-7-tert.-butoxycarbonyl-heptyl amide, 28 mg of HOBt and 57 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system: methylene chloride/methanol/concentrated ammonia 800:50:1). Rf (methylene chloride/methanol/concentrated ammonia 500:50:1)=0.33.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:17]1[C:22]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[NH4+].[Cl-]>CN(C=O)C>[NH2:30][C:25]1[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:22]2[C:17]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH:13]4[CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:24]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)C2CC2)c1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)C3CC3)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a 15 mL RB flask was added N-(5-amino-2-chloropyridin-3-yl)cyclopropanesulfonamide (0.050 g, 0.202 mmol), 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.050 g, 0.242 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m solution in THF (Aldrich) (0.807 mL, 0.807 mmol) was then added to the solution in one portion. The now brugundy color mixture was stirred at 0° C. for 10 min then warmed up to rt for 30 min. The reaction mixture was poured into the beaker which had filled with 15 mL sat. NH4Cl. The resulting mixture was stirred at rt for 15 h. The ppt in the solution mixture was collected by filtration. The solid was rinsed with water and dried opened to the air for 4 h. This crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (60.0 mg). MS (ESI pos. ion) m/z: 433.0. 1H NMR (300 MHz, CDCl3) δ ppm 0.97-1.14 (m, 2H) 1.33 (dd, J=4.60, 1.83 Hz, 2H) 2.51-2.69 (m, 4H) 5.42 (br. s., 2H) 6.75 (s, 1H) 6.92 (dd, J=7.82, 4.90 Hz, 1H) 8.32-8.45 (m, 1H) 8.56 (d, J=2.34 Hz, 1H) 8.76 (d, J=2.34 Hz, 1H) 8.87 (dd, J=7.89, 1.75 Hz, 1H) 12.36 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:25](Cl)[CH:26]=[CH2:27]>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][CH:26]=[CH2:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reactant: C=CCCl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: C=CCOc1nc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)cc1C#N

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 5) (100 mg, 0.297 mMol), silver carbonate (82 mg, 0.297 mMol) and allyl chloride were stirred in a brown vessel in acetone (25 ml) for 48 hours. The reaction mixture was filtered. The filtrate was condensed to give the crude compound as a solid. 6-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-2-[(2-propenyl)oxy]-pyridine-3-carbonitrile was purified by silica gel chromatography and recrystallized from hexane. Anal. Calc'd. for C22H17N2OSF: C, 70.19; H, 4.55; N, 7.44. Found: C, 69.80; H, 4.60; N, 7.32.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.Cl.[NH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20].[BH4-].[Na+]>ClC(Cl)C.CO>[CH3:23][C:18]([NH:17][CH2:14][C:11]1[CH:10]=[CH:9][N:8]=[CH:13][CH:12]=1)([CH3:24])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=Cc1ccncc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(C)(C)NCc1ccncc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1.04 ml of triethylamine and then 0.659 g of pyridine-4-carbaldehyde are successively added to a solution of 0.945 g of methyl α-aminoisobutyrate hydrochloride in 28 ml of dichloroethane. The reaction mixture is stirred overnight at a temperature in the region of 20° C. The mixture is purified by filtration on Merck Lichroprep aminopropyl-grafted silica. The filtrate is concentrated under reduced pressure and the residue thus obtained is taken up in 25 ml of methanol, 0.372 g of sodium borohydride is added. The reaction mixture is stirred for 48 hours at a temperature in the region of 20° C. and then poured into a mixture of a normal solution of sodium hydroxide/ice. The mixture obtained is extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. 0.726 g of methyl 2-methyl-2-[(pyrid-4-ylmethyl)amino]propanoate is thus obtained in the form of an oil, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH3:17][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:13][C:14](=[O:16])[N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:18]
Reactant: C1CCNCC1
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (11.8 g, 46.8 mmol) in DMF (100 mL) was added CDI (7.60 g, 1 equiv, 46.8 mmol) in one portion and stirred at room temperature for 2 h. Piperidine (9.27 mL, 2 equiv, 93.6 mmol) was added and the reaction was left to stir for 17 h. The solvent was removed on a rotovap and the residue was dissolved into a mixture of ethyl acetate (300 mL) and water (100 mL). The organic layer was separated and washed with saturated NaHCO3 solution (2×150 mL), 1 N HCl solution (150 mL) and brine (150 mL). It was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude material was purified on an ISCO system using a 220 g column and ethyl acetate and hexanes as eluent. The desired fractions were collected and concentrated to a colorless oil (8.84 g, 60%). 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 6H), 1.48-1.57 (m, 4H), 1.60-1.66 (m, 2H), 3.40-3.44 (m, 2H), 3.52-3.58 (m, 2H), 5.04 (s, 2H), 6.15 (s, 1H), 7.27-7.37 (m, 5H). LRMS (ESI+) for C18H26N2O3 (318.2); Found: 319 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cc(I)ccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccnc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 66.5 %

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)pyridine [purchased from Matrix Scientific] (2.5 g, 9.16 mmol) and triisopropylborate (2.54 mL, 10.99 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.03 mL, 10.07 mmol). The reaction was stirred at −78° C. for 2½ hours then allowed to warm slowly to −10° C. over 1 hour. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting oily suspension extracted with ether (100 mL). The organic phase was separated, washed with saturated brine (2×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an off-white foam. Ether (12 mL) and hexanes (24 mL) were added and the resulting suspension stirred vigorously for 30 minutes then filtered to give 2-(trifluoromethyl)pyridine-4-boronic acid (1.163 g, 67% yield) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:7]=[CH:6][N:5]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([S:14](Cl)(=O)=O)[CH:13]=2)[N:4]=1.Cl>C(O)(=O)C.[Fe]>[S:14]([C:12]1[CH:13]=[C:8]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:21])([F:1])[F:20])=[N:4]2)[C:9]([CH3:19])=[CH:10][C:11]=1[CH3:18])[S:14][C:12]1[CH:13]=[C:8]([N:5]2[CH:6]=[N:7][C:3]([C:2]([F:21])([F:20])[F:1])=[N:4]2)[C:9]([CH3:19])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(-n2cnc(C(F)(F)F)n2)cc1SSc1cc(-n2cnc(C(F)(F)F)n2)c(C)cc1C
Temperature: 120 °C

Procedure:
A quantity of 2 g of 5-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]-2,4-dimethylbenzenesulphonyl chloride is dissolved in 25 ml of glacial acetic acid, and 4.6 ml of 32% strength hydrochloric acid are added. The mixture is heated to reflux temperature (120° C.). Then 2.53 g of iron powder are added in portions. Following complete reaction, the major fraction of the glacial acetic acid is removed by distillation, and water and dichloromethane are added. Following phase separation and concentration of the organic phase on a rotary evaporator, 1.3 g (80% of theory) of a beige solid are obtained.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][O:11][CH2:12][C:13]#[CH:14])[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[Li+].[OH-]>>[C:1]([NH:4][C@@H:5]([CH2:10][O:11][CH2:12][C:13]#[CH:14])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C#CCOC[C@H](NC(C)=O)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: C#CCOC[C@H](NC(C)=O)C(=O)O
Yield: 92.3 %

Procedure:
Using (S)-methyl 2-acetamido-3-(prop-2-ynyloxy)propanoate (1.00 g, 5.03 mmol) and LiOH (aqueous 0.6 M sol., 8.4 mL, 5.03 mmol), and the preceding procedure gave 0.86 g (93%) of desired product as a yellow oil: Rf=0.35 (15/5/1 EtOAc/hexanes/AcOH); IR (nujol mull) 3270, 2924, 2120, 1729, 1641, 1547, 1459 cm−1; 1H NMR (DMSO-d6) δ 1.87 (s, CH3C(O)), 3.48 (t, J=2.4 Hz, CH2CCH), 3.62 (dd, J=4.1, 9.6 Hz, CHH′OCH2), 3.74 (dd, J=2.4, 9.6 Hz, CHH′OCH2), 4.16 (d, J=2.4 Hz, OCH2C), 4.41-4.47 (m, CH), 8.21-8.23 (d, J=8.4 Hz, NHCH); 13C NMR (DMSO-d6) δ 22.4 (CH3C(O)), 52.1 (CH), 57.8 (CH2CCH), 69.2 (CH2OCH2), 77.6 (CH2CCH), 79.9 (CH2CCH), 169.6, 171.5 (2 C(O)); HRMS (ESI) 186.0760 [M+H+] (calcd. for C8H12NO4 186.0766); Anal. (C8H11NO4, 0.25H2O) Calcd.: C, 50.66%; H, 6.11%; N, 7.38%. Found: C, 50.76%; H, 6.29%; N, 7.10%.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:9][C:10]([O:12]CC)=O)=[O:6])[CH:2]=[CH2:3].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].[H-].[Na+].Cl.C(O)(=O)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[Si:17]([O:16][CH2:15][C@H:8]1[N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:26][CH:25]([C:24]([O:28][CH2:29][CH3:30])=[O:27])[CH:10]([OH:12])[CH2:9]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C=CCOC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(=O)OCC
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [BH3-]C#N
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CC(C(=O)OCC)C(O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of ethyl (3S)-3-{[(allyloxy)carbonyl]amino}-4-{[tert-butyl(dimethyl)silyl]oxy}butanoate (1.25 g, 3.6 mmol) and ethyl acrylate (0.39 ml, 3.6 mmol) in toluene (10 ml) was added at 40° C. sodium hydride (60% suspension in oil, 145 mg, 3.6 mmol). The mixture was stirred at 60° C. for 1 hour and then poured into diluted hydrochloric acid. The solution was extracted three times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was dissolved in methanol(25 ml) and to the solution were added acetic acid (0.25 ml, 4.4 mmol) and sodium cyanoborohydride (0.27 g, 4.3 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue was purified with silica gel chromatography to give 1-allyl 3-ethyl (6S)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxy-1,3-piperidinedicarboxylate (0.48 g, 33%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C#N)=[C:20]([O:26]C)N=1)(C)(C)C.C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1.[BH4-].[Na+]>>[C:1]([C:5]1[N:10]=[C:9]([O:26][CH3:20])[C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)c1ccc(C(C)(C)C)nc1
Reactant: COc1nc(C(C)(C)C)ccc1C#N
Agent: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1nc(C(C)(C)C)ccc1C(C)N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of [1-(6-tert-butylpyridin-3-yl)ethyl]amine starting from 6-tert-butyl-2-methoxynicotinonitrile (intermediate 23) (66 mg, 0.347 mmol), MeMgBr 1.4 M 75/25 toluene/THF (743 μL, 1.04 mmol) and NaBH4 (32.8 mg, 0.87 mmol Material isolated from the workup was used without further purification in the preparation.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:19](OCC)=[O:20])([C:14](OCC)=[O:15])[CH2:10][CH2:9]1>CCOCC>[OH:15][CH2:14][C:11]1([CH2:19][OH:20])[CH2:12][CH2:13][C:8](=[CH2:7])[CH2:9][CH2:10]1
Reactant: C=C1CCC(C(=O)OCC)(C(=O)OCC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=C1CCC(CO)(CO)CC1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
To a suspension of LiAlH4 (0.166 g, 4.4 mmol) in anhydrous Et2O (10 mL) stirred a 0° C. was added a solution of Compound 100a (100 mg, 2.08 mmol) in Et2O (10 mL). The reaction mixture was stirred at r.t. for 2 h. Additional 0.5 equivalents of LiAlH4 were added and the reaction was stirred at r.t. for 1 h. Afterwards, it was quenched, by adding THF/H2O (2 mL:1.3 mL), then 2N HCl (30 mL). Extraction with EtOAc, drying over Na2SO4 and evaporation to dryness afforded a crude, that was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Dichloromethane-Methanol gradient from 1:0 to 95:5) to give the title compound as a white solid. Yield: 92.1%.