Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:39][CH:40]([CH3:54])[CH2:41][C:42]([C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=1)=O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:42]([C:44]2[CH:45]=[CH:46][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=2)[CH2:41][CH:40]([CH3:54])[CH3:39])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)CC(C)C)cc1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=Cc2ccc(Br)cc2)CC(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
4-Bromobenzyltriphenylphosphonium bromide (2.07 g, 4.40 mmol) was suspended in toluene (4.0 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide (4.04 mL, 1.0 M in toluene) was added. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 hour. A solution of Intermediate (10) (180 mg, 0.817 mmol) in toluene (0.8 mL) was then added drop-wise, and the reaction was allowed to stir for 18 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted three times with ethyl acetate. The combined organics were washed twice with 1N HCl and once with brine, then dried over magnesium sulfate, filtered, and concentrated. The crude solid was taken up in heptane and the remaining solids (triphenylphospine oxide) were filtered off. The filtrate was concentrated and purified by column chromatography (0-10% ethyl acetate in heptane) to give methyl 4-(1-(4-bromophenyl)-4-methylpent-1-en-2-yl)benzoate (184.7 mg, 61%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDCl3, δ): 8.04-8.00 (m, 2H), 7.97-7.92 (m, 2H), 7.50-7.46 (m, 4H), 7.22-7.16 (m, 6H), 6.77-6.72 (m, 2H), 6.69 (s, 1H), 6.39 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.58 (d, J=7.4 Hz, 2H), 2.37 (dd, J=7.2, 1.2 Hz, 2H), 1.68-1.57 (m, 1H), 1.51 (dt, J=13.5, 6.8 Hz, 1H), 0.88 (d, J=6.6 Hz, 6H), 0.78 (d, J=6.6 Hz, 6H).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[N:22]1([C:2]2[C:11]([F:12])=[CH:10][C:9]3[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][N:6]4[CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.9 %

Procedure:
2.92 g of the compound (6) obtained in Example 2 (1), 1.07 g of pyrrolidine and 2.25 g of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 20 ml of N,N-dimethylformamide, and the solution was heated at 80° C. for 12 hours. The solvent was removed by distillation, and 100 ml of chloroform was added to the residue. After washing with water, the organic layer was separated from the solution. After drying over magnesium sulfate, the solvent was removed by distillation. To the residue, 50 ml of isopropyl ether was added, and the solid was filtered to obtain 2.60 g of the subject compound (122).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:9][CH:8]=2)[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a solution of methyl 4-[2-((4-fluorophenyl)-2-oxoethyl]benzoate (Example 1, Step 2) (1.0 g, 3.67 mmole) in DMF (10 mL) at 0° C. was added NaH (0.105 mg, 3.6 mmol). After stirring for 10 minutes at 0° C., cinnamyl bromide (0.71 g, 3.6 mmole) was added to the mixture. The reaction was stirred for r.t. for 1 h. and was then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography to yield 1.02 g of the desired product.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[F:28])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[F:28])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[O:14]
Reactant: CC(C)OC(=O)c1ccc(F)c(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)ccc2F)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Thionyl chloride (4.6 g, 0.039 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for about 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the ice-cooled solution treated dropwise with a solution of 1-methylethyl 3-amino-4-fluorobenzoate (7.4 g, 0.037 mole) and triethylamine (3.9 g, 0.039 mole) in methylene chloride (50 ml). The reaction mixture was stirred overnight at room temperature, and then washed in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml), dried with anhydrous sodium sulfate and evaporated. Recrystallization of the solid residue from 100% ethanol (100 ml) gave light brown crystals, m.p. 132°-135° C. (7.8 g, 61% yield).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][O-:11].[Na+]>CO.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:2][O:11][CH3:10])=[CH2:9])[CH3:8]
Reactant: C=C(CBr)C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C(COC)C(=O)OCC
Temperature: 0 °C
Yield: 28.7 %

Procedure:
A solution of ethyl α-(bromomethyl)acrylate (0.99 g, 5.1 mmol [Villieras J., Rambaud M., Synthesis, 1982:924-926]) in methanol (10 mL) is added to an ice-cold solution of sodium methoxide (0.33 g, 6.1 mmol) in methanol (50 mL). The suspension is refluxed for 21 hours, cooled, diluted with water and extracted with dichloromethane. The organic extracts are dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound (0.211 g). 1H NMR (200 MHz, CDCl3): δ 6.33-6.26 (m, 1H), 5.88-5.80 (m, 1H), 4.23 (q, 2H), 4.19-4.10 (m, 2H), 3.41 (s, 311), 1.31 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].[O:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]([O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[C:3]([CH3:12])[CH:4]=1)=[O:19]
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OC(=O)C2CCCO2)cc([N+](=O)[O-])c1N

Procedure:
0.84 g (5.00 mmol) 4-amino-3-methyl-5-nitro-phenol, 0.58 g (5.00 mmol) (R)-tetrahydro-furan-2-carboxylic acid, 1.77 g (5.50 mmol) TBTU and 1.92 mL (11.00 mmol) DIPEA in 10.0 mL DMF were stirred overnight at RT. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic phase was separated off, dried and evaporated down i.vac. The residue was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with an aqueous 1M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: C(O)=O.Cl[S:5]([N:8]=C=O)(=[O:7])=[O:6].[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>ClCCl.CN(C)C(=O)C>[S:5](=[O:6])(=[O:7])([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)[NH2:8]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=CO
Solvent: CC(=O)N(C)C
Product: C[C@]12CC[C@@H]3c4ccc(OS(N)(=O)=O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of formic acid (284.92 mmol) and N,N-dimethyl acetamide (3.03 mmol) was added to a stirred solution of chlorosulfonyl isocyanate (277.47 mmol) in dichloromethane (87.5 ml) at 42° C. within a period of 3.5 hours. The mixture was heated to reflux for 15 minutes and cooled to ambient temperature. The resulting mixture was added to a stirred solution of estrone (184.93 mmol) in N,N-dimethyl acetamide (625 ml) at ambient temperature within a period of 20 minutes. The mixture was stirred at ambient temperature for 17 hours, and then poured onto water (1875 ml). After a while a white precipitate was formed. The suspension was stirred at ambient temperature for another 2 hours, and filtered. The crystals were washed twice with water (250 ml), and used without further drying and purification in the next step (Procedure II). Yield: 87.8 g (wet material) white crystals, purity (HPLC): 99.12%.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([Br:16])[CH:18]=[N:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1cncc(Br)c1)C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of N'-t-butyl-N'-(4-chlorobenzoyl)hydrazine (0.5 g, 0.0022 mol) and 5-bromonicotinic acid (0.44 g, 0.0022 mol) in 10 ml of methylene chloride containing triethylamine (0.33 g) was added to a solution of methanesulfonyl chloride (0.25 g, 0.0022 mol) in 10 ml of methylene chloride at 0° C. The resulting mixture was stirred at 23° C. for 2 hours and then was allowed to stand overnight at 23° C. Aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was re-extracted with methylene chloride. The organic extracts were evaporated to give a yellow solid which was triturated with hexane/methylene chloride to afford N'-t-butyl-N-(5-bromonicotinoyl)-N'-(4-chlorobenzoyl)hydrazine as an off-white solid: m.p. 193°-197° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:6][C:5]=12.[H-].[Na+].[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:25])[C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:6][C:5]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide (0.05 g, 0.150 mmol) in tetrahydrofuran (1.246 ml) was treated with sodium hydride (0.018 g, 0.449 mmol) in 3 portions. The reaction was stirred at ambient temperature for 45 minutes and became a partially homogeneous solution. Benzenesulfonyl chloride (0.021 ml, 0.164 mmol) was added and the mixture was stirred for 16 hours. The reaction was treated with 0.1 mL water and was concentrated under a stream of nitrogen. Reverse-phase chromatography provided the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 8.73 (dd, J=7.0, 0.9 Hz, 1H), 8.15 (dd, J=2.2, 0.8 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.89-7.75 (m, 5H), 7.73-7.59 (m, 3H), 7.46 (dd, J=7.0, 1.6 Hz, 1H), 7.37-7.31 (m, 2H), 4.75 (s, 2H), 3.96-3.88 (m, 2H), 2.67-2.52 (m, 1H), 2.48-2.37 (m, 2H), 1.95-1.72 (m, 4H); MS (ESI(+)) m/e 475 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]O.[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]=1[OH:36])([CH3:25])([CH3:24])[CH3:23].B(F)(F)F.CCOCC.O>O1CCOCC1>[C:32]([C:28]1[CH:29]=[C:30]([CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:31]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:27]=1[OH:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCCC(C)CCCC(C)CCCC(C)C
Yield: 9.1 %

Procedure:
A solution of 3,7,11,15-tetramethyl-2-hexadecen-1-ol (2.97 g;10.0 mmole) in dioxane (8 ml) was dropwise added to a solution of 2,6-di-tert-butyl phenol (4.13 g;200 mmole) and boron trifluoride ethyl etherate (0.86 g;6.0 mmole) in dioxane (20 ml) at 40° C. over one hour. After stirring the resultant solution at that temperature for 2.5 hours, the reaction solution was poured into water (30 ml) and was then extracted once with ethyl acetate (20 ml). The extract was successively washed with 30 ml of 5% (w/v) aqueous sodium hydroxide solution containing 3% (w/v) sodium hydrosulfite (once), 30 ml of water (twice) and then 30 ml of saturated aqueous sodium chloride (once) and was dried over anhydrous magnesium sulfate. Then, the solvent and the unreacted 2,6-di-tert-butyl-phenol were distilled off and the resultant residue was subjected to silica gel column chromatography to obtain 440 mg (0.91 mmole) of 2,6,di-tert-butyl-4-(3,7,11,15,tetramethyl-2 -hexadecenyl)-phenol from the fractions eluted through the column with hexane-ethyl acetate (50:1). Yield=9.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([NH:35][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=2)[N:9]=[CH:8][N:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)ncnc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
7-Chloro-6-nitro-4(3H)-quinazolone [J. Org. Chem., 40, 356 (1975) etc.] (10 g, 54.8 mmol) was added to phosphorus oxychloride (40 ml) under ice-cooling. A temperature of the mixture was gradually raised and the mixture was refluxed for 2 hours. After evaporation of the solvent under reduced pressure, a solution of triethylamine (200 ml, 1.43 mol) and benzylamine (40 ml, 366 mmol) dissolved in tetrahydrofuran (500 ml) was added to the residue under ice-cooling. A temperature of the mixture was raised to room temperature and the mixture was stirred overnight. After evaporation of the solvent under reduced pressure, water and chloroform were added and the organic layer was separated. The aqueous layer was extracted with chloroform and the chloroform layer was combined with the organic layer. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, a mixed solvent of methanol and water was added thereto. The precipitated crystals were filtered off to give the title compound (8.55 g, 49.6%).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.C1COCC1>[Si:11]([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)C#CC1CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH4Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). 1H NMR(CDCl3, 300 MHz) δ1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[O:11])([O-])[O-].[K+].[K+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:1]([CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][CH2:8][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCCl
Reactant: Nc1ccccc1
Agent: [K+]
Product: OCCCCCCN(CCCCCCO)c1ccccc1
Yield: 127 %

Procedure:
A mixture of freshly distilled aniline (93 g, 1.10 mol), potassium carbonate (304 g, 2.2 mol), 6-chloro-1-hexanol (300.0 g, 2.2 mol), and 500 mL of η-butanol was heated at reflux for 82 hours under nitrogen with vigorous stirring. After cooling and filtering, the butanol was evaporated at reduced pressure to leave a tan oil. The oil was fractionally distilled in vacuo, yielding 205 g (70%) of the title compound as a colorless oil, bp 195°-225° C. (0.15 nm).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.241 g, 5.85 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.234 g, 5.85 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.358 mL, 5.85 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.259 g, 61%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.88-2.13 (m, 4H), 2.63-2.83 (m, 2H), 2.99-3.10 (m, 1H), 3.23-3.34 (m, 1H), 3.45 (s, 3H), 3.88-4.00 (m, 1H), 4.35-4.46 (m, 1H), 5.85 (d, 1H), 6.88-7.06 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:41])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccncc1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccncc2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and pyridine-4-boronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCN(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF was added potassium carbonate (4.4 eq.) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.5 eq.). The reaction was heated to 80° C. and stirred for 4 hr. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with 5% aqueous potassium carbonate solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 2%→5% [2 M NH3 in MeOH] in DCM) to afford the title compound as an oil.