Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])/[CH:19]=[CH:18]/[C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.30 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.51 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 174–175° C.
Reaction SMILES: [CH2:1]([N:6]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([OH:32])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:40])=[N-]>CO.C(OCC)C>[CH2:33]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:11]([C:30]([O:32][CH3:40])=[O:31])[CH2:10]1)=[O:8])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C=[N+]=[N-]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)O)C1
Solvent: CCOCC
Solvent: CO
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 368 mg (0.725 mmole) of (S)-4-(dipentylcarbamoyl)-1-(diphenylacetyl)piperazine-2carboxylic acid (from Example 9) in 5 ml of methanol was treated at 0° C. with 20 ml of diazomethane solution in diethyl ether (prepared by the procedure above). The solution was stirred at 0° C. for 30 minutes and at 25° C. for 30 minutes. The excess diazomethane was destroyed by the dropwise addition of acetic acid until the solution became colorless. The resulting solution was concentrated in vacuo and the residue was chromatographed over an 85×2.5 cm LH-20 column and concentrated in vacuo to 225 mg (59%) of pale colored oil which was homogeneous by TLC (1:1 hexane-ethyl acetate, Rf =0.7).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([O-])([O-])[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O>[C:1]([C:9](=[CH:15][O:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Ethyl benzoylacetate (17.0 g, 88.4 mmol) and ethyl orthoformate (106 mL, 637 mmol) were dissolved in acetic anhydride (60.2 mL, 637 mmol) and stirred at 140° C. overnight. The reaction solution was returned to room temperature, then added with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (20.7 g, yield 94%) was obtained as an orange oil.
Reaction SMILES: [CH2:1]([CH:8]([CH:12]([OH:19])[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([CH:8]([CH:12]([OH:19])[C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(O)C(Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 300 mg (1.07 mmol) of the less polar (2R,3R or S)-2-benzyl-3-hydroxy-5,5-dimethyl-4-oxohexanoate and 1.07 ml of 1N sodium hydroxide solution in 10 ml of methanol is stirred at room temperature for 3 hours. Thereafter, the reaction mixture is neutralized with 1.07 ml of 1N hydrochloric acid and evaporated under reduced pressure. The residue is triturated with ethyl acetate and the insoluble solid is separated. After evaporation of the ethyl acetate phase there are obtained 180 mg of (2R,3R or S)-2-benzyl-3-hydroxy-5,5-dimethyl-4-oxohexanoic acid as a colourless solid, MS: 231 (M--CH3 --H2O)+.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: NCCCN
Reactant: Brc1nsc2cccnc12
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCCNc1nsc2cccnc12
Temperature: 25 °C

Procedure:
3-Bromoisothiazolo[4,5-b]pyridine (1.90 g, 8.8 mmol) and 1,3-diaminopropane (6.70 g, 90 mmol) in methanol (15 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water yielded N1-(isothiazolo[4,5-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.55 (d, 1H), 8.05 (d, 1H), 7.32 (dd, 1H), 6.25 (br s, 1H), 3.65 (m, 2H), 2.85 (t, 2H), 1.85 (t, 2H), 1.45 ppm (br s, 2H). MW=208 confirmed by LC-MS, tr=5.91 min (Method Y) MH+=209.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12].[I-:27].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:26])[N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:10](=[O:13])[C:11]=1[CH3:12]
Reactant: [I-]
Reactant: CC1=C(CCCCCCl)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 80 °C
Reaction time: 19 h
Yield: 77.9 %

Procedure:
A mixture of 11.68 g of 4-[3-(5-chloropentyl)-2,5-dihydro-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile and 18.2 g of sodium iodide in 180 ml of ethylmethylketone was stirred under a nitrogen atmosphere for 19 hours at 80° C. After cooling, it was diluted with ethyl acetate and washed with water as well as saturated sodium chloride solution. After drying on sodium sulfate and concentration by evaporation, 11.26 g of the title compound was obtained as a white solid.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17]([O:19][P:20]([CH2:25][C:26](Cl)=[O:27])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:20]([CH2:25][C:26](=[O:27])[NH:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])(=[O:24])[O:19][CH2:17][CH3:18])[CH3:23]
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: Nc1cc(Cl)ccc1C=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(CC(=O)Nc1cc(Cl)ccc1C=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine (3.7 ml, 45.7 mmol) is added to a solution of 2-amino-4-chloro-benzaldehyde (6.18 g, 39.7 mmol) in 170 ml of anhydrous toluene, followed dropwise by a solution of chlorocarbonylmethylphosphonic acid diethyl ester (9.8 g, 45.7 mmol) in 15 ml of anhydrous toluene whilst maintaining the reaction mixture at a temperature of less than 30° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with a 1N HCl solution, and then again with water. Finally the mixture is washed with an aqueous saturated NaCl solution. The organic phase is dried over MgSO4, and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the following step.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C@H:5]1[O:10][C@:9]2([O:15][C@@H:14]3[CH2:16][CH:17]=[C:18]([CH3:41])[C@@H:19]([OH:40])[C@@H:20]([CH3:39])[CH:21]=[CH:22][CH:23]=[C:24]4[CH2:25][O:26][C@@H:27]5[C@H:32]([OH:33])[C:31]([CH3:34])=[CH:30][C@@H:29]([C:35]([O:37][C@@H:12]([CH2:13]3)[CH2:11]2)=[O:36])[C@:28]45[OH:38])[CH:8]=[CH:7][C@@H:6]1[CH3:42])[CH3:4].CCC([C@H]1[O:52][C@]2(O[C@@H]3CC=C(C)[C@@H](O[C@@H]4O[C@@H](C)[C@H](O)[C@@H](OC)C4)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(O[C@@H](C3)C2)=O)[C@]45O)C=C[C@@H]1C)C>>[CH3:1][CH2:2][CH:3]([C@H:5]1[O:10][C@:9]2([O:15][C@@H:14]3[CH2:16][CH:17]=[C:18]([CH3:41])[C@@H:19]([OH:40])[C@@H:20]([CH3:39])[CH:21]=[CH:22][CH:23]=[C:24]4[CH2:25][O:26][C@@H:27]5[C@H:32]([OH:33])[C:31]([CH3:34])=[CH:30][C@@H:29]([C:35]([O:37][C@@H:12]([CH2:13]3)[CH2:11]2)=[O:36])[C@:28]45[OH:38])[CH2:8][C@H:7]([OH:52])[C@@H:6]1[CH3:42])[CH3:4]
Reactant: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O)[C@H](C)O3)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Reactant: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@@H](O)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](C/C=C(\C)[C@@H](O)[C@@H](C)/C=C/C=C4\CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(=O)O3)[C@]45O)O2)C[C@H](O)[C@@H]1C
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)[C@@H](O)[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CCC(C)[C@H]1O[C@]2(C=C[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)[C@@H](O[C@H]3C[C@H](OC)[C@@H](O)[C@H](C)O3)[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Product: CCC(C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](CC=C(C)[C@@H](O)[C@@H](C)C=CC=C4CO[C@@H]5[C@H](O)C(C)=C[C@@H](C(=O)O3)[C@]45O)O2)C[C@H](O)[C@@H]1C

Procedure:
13β-14a-hydroxy, avermectin B1a aglycone→13β-14a-hydroxy, avermectin B1a monosaccharide
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncc2ncnc(O)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1
Temperature: 100 °C

Procedure:
148 g of 4-hydroxy-6-methylthiopyrimido[5,4-d]pyrimidine, 286 ml of hexamethyldisilazane, 333 g of 3-chloro-4-fluoroaniline and 15 g of p-toluenesulphonic acid are heated at 140° C. for 23 hours. The reaction mixture is cooled and, after addition of 4 1 of methanol, heated at 100° C. for one hour. The methanol is distilled off and the residue is triturated three times with diethyl ether and filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:11]O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[N+:9]([O-:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccncc1F
Reactant: OO
Solvent: CC(=O)O
Product: O=C(O)c1cc[n+]([O-])cc1F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoroisonicotinic acid (5.0 g, 35.33 mmol) in acetic acid (25 ml) was added hydrogen peroxide (6 ml). The reaction mixture was stirred at 70-80° C. overnight. The solvent was removed to obtain 5.5 g of 3-fluoroisonicotinic acid 1-oxide in quantitative yield.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]([CH:11]2[S:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:28]([Si](C)(C)C)[C:29](=[O:34])C(F)(F)F)(C)C.ClC(Cl)(Cl)C(N=C=O)=O>ClCCl>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([CH:11]2[S:16][CH2:15][CH2:14][N:13]([C:29](=[O:34])[NH2:28])[C:12]2=[O:17])=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NCCSC1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)N1CCSC(C(=O)OC(c2ccccc2)c2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 2-diphenylmethoxycarbonyl-3-oxothiomorpholine (327 mg, 1 mM), dichloromethane (8 ml), and bistrimethylsilyltrifluoroacetamide (0.53 ml). After 30 minutes' stirring from addition of trichloroacetyl isocyanate (0.18 ml), another trichloroacetyl isocyanate (0.06 ml) is added. After another 30 minutes' stirring, the mixture is concentrated and subjected to silica gel chromatography. Fractions eluted with dichloromethane and a mixture of dichloromethane and ethyl acetate (9:1) are combined and concentrated to give 2-diphenylmethoxycarbonyl-4-carbamoyl-3-oxothiomorpholine (332 mg). Yield 89.6%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCBr
Reactant: CNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCCBr)c1ccccc1
Yield: 37.7 %

Procedure:
N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 9a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:3]1[CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23].[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH3:30].[Cl-].[NH4+]>O1CCCC1>[OH:15][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])/[CH:8]=[CH:7]/[C@H:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCC[Mg]Br
Reactant: CCCCCC(=O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)(/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)O)CCCCC
Reaction time: 1 h

Procedure:
To a −24° C. tetrahydrofuran (38 mL) solution of enone (from Example 1, step 3, 1.52 g) was treated with n-pentylmagnesium bromide (1.8 mL, 2 M ether solution from Aldrich). After 1 hour, the mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. Following drying and filtration, the desired alcohol (780 mg) was obtained after silica gel chromatography (elute with 5% methanol in ethyl acetate).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[NH:12][C:13]([CH2:16][CH2:17][C:18]3[N:19]([S:29]([N:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH:20]=[C:21]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][CH3:26])[N:22]=3)=[N:14][N:15]=2)[CH:7]=[CH:8][C:9]=1[F:10].[CH3:35]I>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:11]2[N:12]=[C:13]([CH2:16][CH2:17][C:18]3[N:19]([S:29]([N:32]([CH3:33])[CH3:34])(=[O:30])=[O:31])[CH:20]=[C:21]([CH2:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH3:26])[N:22]=3)[N:14]([CH3:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CI
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCc2nnc(-c3ccc(F)c(F)c3)[nH]2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCc2nc(-c3ccc(F)c(F)c3)nn2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (21 mg, 0.87 mmol) was added to a solution of 2-{2-[5-(3,4-difluorophenyl)-4H-1,2,4-triazol-3-yl]ethyl}-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (135 mg, 0.29 mmol) in DMF (4 mL) at 0° C., and the reaction was stirred at rt for 30 min. Methyliodide (0.09 mL, 1.4 mmol) was added and stirring continued for 1 hr. The reaction mixture was partitioned between water and diethyl ether. The organic phase was washed with water and brine, dried (sodium sulfate) and concentrated to give a residue. Chromatography of the residue over silica gel (eluting with 60-100% ethyl acetate/hexane) afforded 2-{2-[3-(3,4-difluorophenyl)-1-methyl-1H-1,2,4-triazol-5-yl]ethyl}-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide as an off-white solid.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH2:8][Cl:9])[CH2:5][CH3:6])[CH3:3].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O.C(O)C>[ClH:9].[CH2:5]([N:4]([CH2:7][CH2:8][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]2[CH:23]=[CH:24][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:21][CH:20]=1)[CH2:2][CH3:3])[CH3:6]
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 82.6 %

Procedure:
A solution of 13.2 g (0.075 mol) of 2-(N,N-diethylamino)-1-chloroethane hydrochloride in 30 ml of water is run over the course of 30 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)-phenol and 6.3 g (0.157 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 1 hour and the ethanol is evaporated under reduced pressure. The aqueous phase is extracted with diethyl ether and the organic phase obtained is washed with water until neutral, dried over dry sodium sulphate and evaporated to dryness under reduced pressure. The oily residue is treated in a solution of hydrogen chloride in diethyl ether, to give 20 g of a white powder. Recrystallisation from ethyl acetate gives 18 g of CRL 40 330
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[N+:20]=[N-:21]
Reactant: O=C1c2ccccc2C(=O)N1OCCOCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOCCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
To 1 mL of DMF/H2O (v/v=9/1) was added 2-(2-(2-bromoethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 0.17 mmol) and sodium azide (16.6 mg, 0.26 mmol). The mixture was heated to 80° C. overnight. Then it was allowed to cool down to room temperature and was extracted with ethyl acetate for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 2:1) to afford 2-(2-(2-azidoethoxy)ethoxy)isoindoline-1,3-dione (44 mg, 0.17 mmol, 100%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.28 (t, J=4.7 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H), 3.84 (t, J=3.8 Hz, 2H), 4.34 (t, J=3.9 Hz, 2H), 7.71 (dd, J=2.6, 4.7 Hz, 2H), 7.79 (dd, J=3.2, 5.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.C(N(CC)C(C)C)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>ClCCl>[OH:4][C@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][NH:1][C:50]([N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:51]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: O=C(Cl)N1CCOCC1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a solution of 100 mg (0.41 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.070 mL (0.41 mmol) of N,N-diisopropylethylamine in 2 mL dichloromethane was added 0.050 mL (0.41 mmol) 4-morpholinecarbonyl chloride. The reaction mixture was stirred at room temperature for 18 h, diluted with dichloromethane, and washed with 1N hydrochloric acid and brine. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with ethyl acetate to afford 130 mg (89%) of tert-butyl (1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 6.55–6.36 (m, 2H), 5.00–4.65 (m, 1H), 3.60-3.23 (m, 9H), 3.10–2.80 (m, 2H), 1.40–1.05 (m, 15 H), 0.87 (m, 1H); ES-LCMS m/z 382 (M+Na).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][C:23]=2[OH:34])[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][C:23]=2[O:34][CH2:2][CH2:3][CH3:4])[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC)c1
Temperature: 60 °C

Procedure:
100 μL (1.0 mmol, 1.5 eq) of 1-iodopropane are added to a solution of 285 mg (0.67 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 200 mg (1.45 mmol, 2.2 eq) of potassium carbonate. The reaction medium is heated at 60° C. for 16 hours. The solid is filtered off and the solvent is evaporated off. The methyl 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoate obtained in oil form is used in the following reaction without further purification.