Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)=O.[OH:16][C@@H:17]1[CH2:21][N:20]([C:22](=[O:32])[C@@H:23]([NH:27][C:28]([O:30][CH3:31])=[O:29])[CH:24]([CH3:26])[CH3:25])[C@H:19]([C:33]2[NH:34][CH:35]=[C:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[CH:44]=[C:43]([C:48]3[CH:53]=[CH:52][C:51]([C:54]5[NH:58][C:57]([C@@H:59]6[CH2:63][CH2:62][CH2:61][N:60]6C(OC(C)(C)C)=O)=[N:56][CH:55]=5)=[CH:50][CH:49]=3)[CH:42]=[CH:41]4)[N:37]=2)[CH2:18]1.O[C@@H:72]1CN(C(=O)[C@@H](NC(OC)=O)C(C)C)[C@H](C2NC=C(C3C=CC(C4C=C5C(=CC=4)C=C(C4NC([C@@H]6CCCN6C(OC(C)(C)C)=O)=NC=4)C=C5)=CC=3)N=2)C1>>[CH3:31][O:30][C:28](=[O:29])[NH:27][CH:23]([C:22]([N:20]1[CH2:21][C:17](=[O:16])[CH2:18][CH:19]1[C:33]1[NH:34][CH:35]=[C:36]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([C:48]4[CH:53]=[CH:52][C:51]([C:54]5[NH:58][C:57]([CH:59]6[CH2:63][CH2:62][CH2:61][N:60]6[C:7](=[O:9])[CH:6]([N:5]([CH3:3])[CH3:72])[C:10]6[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=6)=[N:56][CH:55]=5)=[CH:50][CH:49]=4)[CH:44]=3)[CH:39]=2)[N:37]=1)=[O:32])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CC(=O)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(c6ccccc6)N(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C

Procedure:
[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following Example BN substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid and (S)-tert-butyl 2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate for (S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate. C47H50N8O5 calculated 806.4 observed [M+1]+ 807.3; rt=1.55 min.
Reaction SMILES: [Ni:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=[O:6])[CH3:3].[N+]([O-])([O-])=O.[Na+]>O>[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3].[Ni+2:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3]
Reactant: [Ni]
Reactant: CCCCC(CC)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]
Product: [Ni+2]
Temperature: 95 °C

Procedure:
A mixture of 50 grams (0.852 mole) of powdered nickel (particle size 3 to 7 microns), 250 grams (1.724 moles) of 2-ethylhexanoic acid (acid number, 387), a catalyst solution prepared by dissolving 10 grams of sodium nitrate in 25 grams of water, and 170 grams of mineral spirits was agitated and heated to 95° C. The reaction mixture was maintained at 90°-95° C. for 16 hours while it was sparged with air at the rate of 30 liters per hour. It was then heated to 135° C. under vacuum to remove water from it. After the reaction product had been filtered and diluted with mineral spirits, there was obtained a solution of nickel 2-ethylhexanoate in mineral spirits that contained 10% by weight of nickel and had an acid number of 39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1.NC1C=CC=CC=1>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1ccccc1N
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
2-Methoxyaniline (o-anisidine) (15 g, 0.122 mol) was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (50 g, 0.122 mol) by dissolving the aniline in 250 ml of methylene chloride, chilling the solution to -10°, and slowly adding and brominating agent, keeping the temperature below -5°. The reaction was allowed to warm at room temperature, and then washed with 2N sodium hydroxide (2×75 ml), then washed with water (2×25 ml), dried over magnesium sulfate, and evaporated to dryness. The product was purified on a silica gel column, eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether). Anal. Calcd for C7H8BrNO: C, 41.61; H, 3.99; Br, 39.55; N, 6.93. Found: C, 41.59; H, 3.99; Br, 39.49; N, 6.92.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1ccccc1-c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
0.01 mol of 4'-hydroxybiphenylcarboxylic acid and 0.02 mol of potassium hydroxide were dissolved in a mixture of 300 ml of alcohol and 30 ml of water. Then, 1.2 ml of n-octyl bromide was added thereto, and the resultant mixture was refluxed for 12 hours. A 10% potassium hydroxide solution containing 1.12 g of KOH was added and the resultant mixture was refluxed for 2 hours to cause hydrolysis. The product was recrystallized in a mixture of ethanol and glacial acetic acid to obtain 4'-n-octyloxybiphenyl carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:9].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([C:29]1[C:28]([CH3:35])=[N:1][C:2]2[C:3]([C:25]=1[NH2:26])=[C:4]([O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:9])[CH:22]=[CH:23][CH:24]=2)=[O:31])[CH3:34]
Reactant: COc1cccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)c1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46b) and ethyl 3-oxobutanoate as a yellow solid (42%). MS 466 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[BrH:9].[NH+]1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Br
Reactant: Cc1ccnc(N)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Cc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
In a nitrogen atmosphere, 1.08 g of 2-amino-4-methylpyridine was dissolved in 75 mL of tetrahydrofuran, and tetrahydrofuran (75 mL) solution of 3.20 g of pyridinium hydrobromide perbromide was dropwise added thereto at room temperature, over 1.5 hours. After the addition, this was stirred at room temperature for 40 minutes, and 100 mL of aqueous saturated sodium sulfite solution was added to the reaction mixture. This was extracted with ethyl acetate, and the ethyl acetate layer was dried with magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain 1.00 g of the entitled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:30])([F:29])[CH2:27]I>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC(F)(F)F
Temperature: 70 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.4 g, 1.311 mmol), potassium carbonate (0.544 g, 3.93 mmol) and 1,1,1-trifluoro-2-iodoethane (0.826 g, 3.93 mmol) in DMF (2 ml) was heated at 70° C. under stirring for 18 h The reaction mixture was cooled down and diluted with water (15 ml) and extracted with DCM (15 mlX3). The combined organic phase was washed with water (25 ml) and dried with Na2SO4 and concentrated. The residue was purified by column chromatography (biotage 25 g) eluted with ethyl acetate/cyclohexane 0-60% to afford product 6-bromo-7-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.17 g) 1H NMR (500 MHz, CDCl3) 7.45-7.50 (m, 3H), 7.38-7.40 (m, 2H), 7.28 (s, 1H), 4.94 (s, 2H), 4.55 (q, 2H).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([CH3:11])[CH3:10].[CH3:19][S:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:20][CH3:21])[C:13]=1[NH2:14])([CH3:11])[CH3:10]
Reactant: CSC
Reactant: CC(C)c1ccccc1N
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CSCc1cccc(C(C)C)c1N
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
15.51 g (116 mmol) of N-chlorosuccinimide were added over a period of 20 minutes to a solution of 11.2 g (82.9 mmol) of 2-isopropylaniline and 7.22 g (116 mmol) of dimethyl sulfide in 200 ml of methylene chloride, whilst maintaining the internal temperature at between 15° and 20° C. After 15 minutes, 11.73 g (116 mmol) of triethylamine were added to the mixture, which was then heated under reflux for 9 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with diethyl ether and insoluble materials which appeared were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through 300 g of silica gel, using a gradient elution method, with mixtures of hexane and methylene chloride ranging from 4:1 to 0:1 as the eluent, to give 10.45 g (yield 65%) of the title sulfide derivative as an oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[S:2]1.C(N(CC)CC)C.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>C1(C)C=CC=CC=1.CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[O:13])[S:2]1
Reactant: O=C(O)CCCCCC1CCSS1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CNC(=O)CCCCCC1CCSS1
Yield: 13.2 %

Procedure:
The reaction was carried out as described in Example 47, but using 5 ml of a solution of 1.6 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 373 mg of N,N'-carbonyldiimidazole, 0.25 ml of triethylamine and 199 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2:1 and 3:1 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2:3 and 1:1 by volume mixtures of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 61 mg of the title compound as a pale yellow amorphous substance having an Rf value of 0.28 (silica gel thin layer chromatography; using 2:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)=[O:22]>>[CH:21]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=CO
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Product: O=COCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 91 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.2 g, 4.5 mmoles) was added to formic acid (10 ml) and the mixture was refluxed for 7 hours. After cooling, the mixture was concentrated under reduced pressure and the resulting oil was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the eluent to give 1-formyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (1.2 g, 91%) (Compound Id-20) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>CC#N>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[C:7]([Br:14])[CH:6]=1)[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 4-aminophenylacetate (1.79 g, 10 mmol, 1 eq.) in MeCN (50 mL), N-bromsuccinimide (1.78 g, 10 mmol, 1 eq.) was added slowly. The mixture was stirred at r.t. for 72 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (50 mL) and Et2O (50 mL). The org. phase was washed with sat. aq. NaCl soln. (1×50 mL), dried over MgSO4, and concentrated in vacuo to give (4-amino-3-bromo-phenyl)-acetic acid ethyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1
Reactant: CCN=C=O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.56 g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine was dissolved in dry dichloromethane (20 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was stirred with water, the precipitate was filtered, giving the title compound (0.33 g, 65%). Melting point: 235-8° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH:23]1[CH3:29])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([N:22]1[CH:23]([CH3:29])[CH2:24][CH2:25][CH:26]2[CH:27]([O:9]2)[CH2:28]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CCC=CCN1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1CCC2OC2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
m-Chloro-perbenzoic acid (1.05 g, 57-86% pure) was added to a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.83 g, 3.34 mmol) in CH2Cl2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.3 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexanes) to give racemic (1S,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.44 g, 50%) and the title compound as a racemic mixture of the title compound (0.15 g, 17% yield): 1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H, d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=262.0.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[N:13]([CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:12]=[C:11]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.S1C=CC=C1>C1COCC1.[Ni]>[F:32][C:24]1[CH:23]=[C:22]([NH:21][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[CH3:8])[N:13]([CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:12]=2)[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=1
Reactant: Cc1c(-c2cc(Nc3cc(F)cc(C(F)(F)F)c3)nn2CCC(=O)N(C)C)ccnc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccsc1
Product: Cc1cnccc1-c1cc(Nc2cc(F)cc(C(F)(F)F)c2)nn1CCC(=O)N(C)C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
E1 (0.40 g; 0.85 mmol) was dissolved in THF (50 ml) and then Et3N (0.5 ml), 10%, RaNi (0.1 g) and thiophene solution (0.1 ml) were added. The reaction mixture was stirred under H2 pressure overnight. The solvent was evaporated in vacuo and then H2O (10 ml) was added. The water phase was extracted by EtOAc (3×30 ml), the combined organic layers were washed by brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 mobile phases was applied. Phase A: a 0.25% NH4HCO3 solution in water; phase B: CH3CN). The fractions were collected and worked-up. The desired fraction yielded 0.25 g of E9 (67.55%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1(C)C=CC=CC=1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>C1COCC1.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: Clc1ccccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccccn2)cn1
Temperature: 27.5 °C
Reaction time: 8 h

Procedure:
1.09 kg=0.75 L (1.1 equiv., d=1.453 g/ml) of 5-bromo-2-methoxy pyridine and 3.60 L (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, were loaded into a reactor A previously dried under nitrogen. The mixture was heated to 25-30° C. and added with 5.70 kg (1.485 equiv.) of a solution of Isopropyl magnesium chloride lithium chloride complex (20% wt/wt) in THF over about 1 h. It was stirred at 25-30° C. for at least 8 hours (the reaction may be conducted overnight). The conversion was monitored via HPLC. When the reaction was complete, a mixture of 9.67 g of Pd(dppf)C12 (0.25 mol %), 0.60 kg equal to 0.50 l (1 equiv., d=1.2 g/ml) of 2-chloropyridine and 3.60 l (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, was loaded into a reactor B, previously dried and kept under a flow of nitrogen. The mixture was stirred at 45-50° C. for 30 min. The suspension of Grignard reagent from reactor A was transferred into reactor B over approximately 1 hr, while keeping the T at 45-50° C. Upon completion, stirring was prosecuted for at least 4 hr at 45-50° C. The conversion was monitored in HPLC (>99%; HPLC purity A/A % of the product >94%). When the reaction was complete, the mixture was cooled to 25-30° C., added with 3.60 L (6 V) of purified water carefully, keeping the temperature at 20-25° C., over about 30 min.-1 hr. Stirring was prosecuted for 15 min. The biphasic mixture was filtered on paper and the solid residue was washed with 0.60 L (1 V) of toluene. The filtrate was loaded into the reactor C. The organic phase (containing the reaction product) was separated. 3.60 L (6 V) of purified water were added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase (containing the reaction product) was recovered. A solution of Hydrochloric acid 4 M, prepared by using 1.41 L (2.35 V) of concentrated hydrochloric acid and 2.06 L (3.44V) of purified water, was added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the aqueous acid phase (the product was in aqueous phase) was separated. The acid aqueous phase (containing the product) was washed twice with 1.20 L (2×2V) of MTBE. The aqueous phase was separated and weighed. Determination of the yield in solution of 2-methoxy-5-(pyridine-2-yl)pyridine was made by external standard HPLC analysis (molar yield in solution: 90.3%):
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.CI>C1COCC1>[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:1])[CH2:15]1
Reactant: [Li]CCCC
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1CC(c2ccccc2)(N(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF in argon and mixed with n-butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at 30° C. The reaction mixture was cooled to −78° C. 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in 10 ml of dry THF, was added in drops to this solution within 10 min. The batch was stirred for 30 min at −78° C. and then mixed with methyl iodide (1.86 ml, 30 mmol). It was heated to RT and stirred for a further 18 h. The solvent was removed at the rotary evaporator and the residue taken up in DCM. Extraction was conducted with 1N HCl (3×30 ml). The aqueous phase was basified with 5N NaOH (20 ml) and extracted with DCM (3×30 ml). The combined organic phases were washed with H2O (2×10 ml) and dried over Na2SO4. The semisolid residue (1.2 g) obtained after removal of the solvent was recrystallised from ethyl acetate (1 ml).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[CH:21]=[CH:20][C:19](C(OCC)=O)=[CH:18][CH:17]=2)O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:27].[Na+].Cl.[CH3:30][OH:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:30]([OH:31])=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(C(C(=O)O)c2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a stirring solution of 4-[(4-ethoxycarbonyl-phenyl-)hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.145 g, 6.18 mmol) in methanol (30 mL) is added 10 mL of 1N aqueous NaOH and the reaction is heated in a 50° C. bath for 1 hour. The reaction is cooled to 0° C. and carefully acidified with 1N aqueous HCl. The reaction is extracted with dichloromethane (DCM), dried over MgSO4, filtered and concentrated to give 1.34 grams of 4-(carboxy-benzyl)-piperidine-1-carboxylic acid tert-butyl ester.