Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
The dihydropyridazinone product from Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a solid which was eluted through a short pad of silica gel with ethyl acetate. The title compound was crystallized from ethyl acetate/hexanes (yield: 35 mg, 75%). mp 255-256° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.16-7.23 (m, 2H), 7.35 (d, J=9Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 345 (M+H)+ and m/z 362 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.4 %

Procedure:
To a solution of ethyl 3-(4-amino-2-fluorophenyl)propanoate (1.48 g, 7.00 mmol) and 4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.09 g, 7.00 mmol) in toluene (15 mL) were added molecular sieves (0.4 nm, beads, 3.5 g), and the mixture was stirred at room temperature for 30 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (20 mL), 10% palladium-carbon (50% water-containing product, 0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 12 hr. The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (2.88 g, yield 83%) as a colorless oil.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])C.BrC[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH2:12]([O:11][C:10](=[O:21])[CH:6]([C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])[CH2:5][CH2:4][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCC(=O)N1C(=O)OCC1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 67 (5.0 g, 16.38 mmol) in anhydrous THF (160 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 16.4 mL, 16.4 mmol) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (10 mL) was slowly injected. After stirring for 1 h at −78° C. and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times with ethyl acetate. The recombined organic layer was successively extracted with brine, a saturated sodium hydrogen carbonate solution, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude product was flashed with 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.24(t, J=7.2, 3H); 1.44(s, 9H); 2.54(m, 2H); 2.77(m, 3H); 3.31(m, 1H); 4.14(m, 4H); 4.43(m, 1H); 4.69(m, 1H); 7.26(m 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=O)=[CH:4][CH:3]=1.C(O)C[OH:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:12]([C:13]([O:15][CH2:16][CH2:17][OH:22])=[O:14])[NH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1
Reactant: OCCO
Product: O=C(OCCO)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C

Procedure:
2-(4-Chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde (2 g.) was boiled in 5 ml. of ethylene glycol for 15 minutes. The reaction was cooled to room temperature, diluted with 10 ml. of water and product extracted into 10 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil (1.5 g.). The oil chromatographed on approximately 100 ml. of silica gel with ethyl acetate-1/hexane-1 as eluant, monitored by thin layer chromatography. Evaporation of middle fractions are ethyl 4-(4-chlorophenoxy)pyrrole-2-carboxylate (100 mg., oil, m/e 281, Rf 0.65 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant; Rf 0.3 with ethyl acetate-1/hexane-1 as eluant). Repeat on a 5.5 g. scale gave an additional 400 mg. of product.
Reaction SMILES: CN(C)C=O.[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([OH:8])=[O:7].[OH-].C[N+](C)(C)C.[CH2:30](Br)[CH3:31]>CO>[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:11]1=[S:23])([O:8][CH2:30][CH3:31])=[O:7]
Reactant: CCBr
Reactant: O=C(O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)CN1C(=O)C(=Cc2ccccc2)SC1=S
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of nitrogen, 4.2 ml of anhydrous N,N-dimethylformamide was added dropwise to 0.279 g of 3-carboxymethyl-5-benzylidenerhodanine (prepared as described in Example 1) at room temperature, and then 1.14 ml of methanol solution of 91.15 mg of tetramethylammonium hydroxide was added dropwise. After the mixture was stirred at room temperature for 20-30 minutes, 0.075 ml of ethyl bromide was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for about 2 hours, and then concentrated under reduced pressure. The residue was diluted with 15 ml of water and extracted with ethyl acetate. The extract was washed with 50 ml of aqueous solution of sodium bicarbonate, 50 ml of water and 50 ml of aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane (1:3) to obtain 14 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])[C:5]2[N:6]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Reaction time: 0.5 h

Procedure:
24 g of 5-bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 20A; 76.2 mmol; 1 equivalent) were initially charged in 400 ml of ethanol, 16 g of powdered molecular sieve 3 Å and 52.7 ml of ethyl 2-chloroacetoacetate (380.8 mmol; 5 equivalents) were added and the mixture was heated at reflux overnight. A further 8 g of molecular sieve were added, and the mixture was heated at reflux for a further 24 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane and chromatographed on silica gel (dichloromethane/methanol 20:1 as mobile phase). The product-containing fractions were concentrated and the residue was stirred with 100 ml of diethyl ether for 30 min, filtered off, washed with a little diethyl ether and dried. This gave 15 g (45% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of methyl 4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (0.80 g), potassium carbonate (0.40 g), vanillin (0.44 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 4-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (1.02 g, 92%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 185-186° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12](=[O:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C.O>CO>[OH:10][CH2:11][C:12](=[O:33])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][CH:22]=[CH:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium carbonate in methanol (190 ml; 0.19M) was added to a suspension of (5α)-21-(acetyloxy)pregn-2-ene-11,20-dione and its 3-ene-isomer (18.8 g) in methanol (188 ml). The resulting solution was stirred at room temperature for 30 min and poured into water (3.7 l). The mixture was extracted with dichloromethane and the organic phase was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give a mixture (3:1) (15.3 g) of (5α)-21-hydroxypregn-2-ene-11,20-dione and its 3-ene-isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(-n2cccc2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(-n3cccc3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of 3-fluoro-4-(1H-pyrrol-1-yl)aniline (0.80 g, 4.55 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (23 mL, 23 mmol, 1 M in heptane) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (785 mg, 5.0 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:2) to give the title compound as a pale yellow solid (450 mg, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
To a solution of 2-(4-methoxyphenyl)acetic acid (10 g, 0.06 mol) in PPA (20 mL) was added dropwise phenol (5.6 g, 0.06 mol) under an inert atmosphere. The mixture was then stirred at 80° C. for 1 h, quenched with cold water and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to obtain the crude product which was purified via silica gel column chromatography to afford 1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)-ethanone (3 g, 20%) as a pale yellow solid
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]([O:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[C:15]1=[O:23])(=[O:12])[CH3:11].[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[N:26]1[CH2:32][CH2:33][NH:34][C:20](=[O:22])[CH2:19][N:16]1[CH2:17][CH2:18][CH:14]([O:13][C:10](=[O:12])[CH3:11])[C:15]1=[O:23]
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.81 g of 2-chloro-1-methyl-pyridinium iodide are suspended in 10 ml of methylene chloride and thereto there are added at room temperature 1.20 of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid. Within 15 minutes there is added dropwise at 0° a solution of 0.98 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine and 3.02 ml of triethylamine in 20 ml of methylene chloride, whereupon the mixture is stirred at room temperature for 18 hours. Thereupon, the mixture is evaporated and the residue is chromatographed on aluminum oxide (activity grade III, neutral). The material which is eluted with chloroform is chromatographed on silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrroldinyl)acetamide which is eluted with alcohol has a melting point of 120°-122° after crystallization from diethyl ether.
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(CO)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(CO)ccc2o1
Yield: 101.9 %

Procedure:
4-[1-Ethyl-1-(5-hydroxymethyl-benzofuran-2-yl)-propyl]-2-methyl-phenol (653 mg, 2.02 mmol) and 1-bromopinacolone (555 mg, 3.10 mmol) and K2CO3 (570 mg, 4.13 mmol) in acetone (40 mL) are reacted analogous to Example 18-E to give the title compound (870 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH2:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH:33]([C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH2:30][CH2:31][NH:32][S:12]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc2cnccc12
Reactant: COc1ccc(C(c2ccc(OC)cc2)N(CCN)CCCOc2ccc(Cl)cc2Cc2ccccc2)cc1
Product: COc1ccc(C(c2ccc(OC)cc2)N(CCCOc2ccc(Cl)cc2Cc2ccccc2)CCNS(=O)(=O)c2cc(Br)cc3cnccc23)cc1

Procedure:
Using a procedure analogous to Preparation 103, reaction of 7-bromo-isoquinoline -5-sulfonyl chloride with N1-[3-(2-benzyl-4-chloro-phenoxy)-propyl]-N1-[bis-(4-methoxy-phenyl)-methyl]-ethane-1,2-diamine provides the title compound as a foam. ESIMS: m/z 814[(M+H)+, 35Cl, 79Br], 816 [(M+H)+, 37Cl, 79Br or 35Cl, 81Br], 818 [(M+H)+, 37Cl, 81Br].
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.C([O:10][C:11](=O)[CH2:12][N:13](C1C=CC=CC=1)[C:14](=[O:29])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)C>C(O)C>[O:29]=[C:14]1[NH:13][CH:12]([C:7]2[CH:6]=[CH:18][CH:17]=[CH:16][CH:21]=2)[C:11](=[O:10])[N:15]1[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][CH2:17]1
Reactant: CCOC(=O)CN(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NC(c3ccccc3)C2=O)CC1
Reaction time: 3 h
Yield: 81 %

Procedure:
Triethylamine (200 μL, 1.43 mmol) was added to a solution of tert-butyl 4-(3-(2-ethoxy-2-oxoethyl)-3-phenylureido)piperidine-1-carboxylate (90 mg, 0.22 mmol) in ethanol (1.8 mL). Reaction was held at 60° C. with stirring for 3 hours. Reaction mixture was concentrated in vacuo. Reside was treated with dichloromethane (20 mL) and then concentrated in vacuo. Title compound was obtained as white solid in 81% yield. MS m/e (M−C4H8+H)+=304.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]1COCC1>>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Alcohol Compound 40 (48.8 g, 0.16 mmol) was added to a mixture of NaH (4.0 g, 0.17 mol) in dry THF (500 mL). After 5 min, Mel (10 mL, 0.17 mol) was added and, after another 3 hours, the mixture was quenched with H2O (150 mL), extracted into diethyl ether (500 mL), dried (MgSO4) and concentrated. Purification of the residue by silica-gel column chromatography [eluent: hexane/ethyl acetate, 90/10, v/v] yielded 1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 41) (37 g, 74%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O.CC#N.CC#N.Cl[Pd]Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=1
Reactant: FC(F)(F)c1cncc(Cl)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 10 %

Procedure:
Charge a sealed tube under a positive pressure of argon with bis(acetonitrile)palladium (II) chloride (18 mg, 0.07 mmol), 2-dicyclohexylphosphino diphenyl (73 mg, 0.21 mmol), cesium carbonate (0.557 g, 1.71 mmol) and 3-chloro-5-trifluoromethylpyridine, (prepared essentially as described in PREPARATION 7), (0.12 g, 0.66 mmol) in acetonitrile and stir at room temperature for 25 min (Angew. Chem. Int. Ed. 42, 5993-5996, (2003)). Add phenylacetylene (0.1 mL, 0.86 mmol) and stir at 100° C. for 16 h. Cool to room temperature, dilute with water, and wash twice with ethyl acetate. Combine the ethyl acetate layers, dry (sodium sulfate), and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 50:50 hexanes:dichloromethane, to obtain the title compound (30 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14].C([O-])(O)=O.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@@H:12]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Yield: 80.1 %

Procedure:
2-Chloro-4-fluorobenzonitrile (2.13 g, 13.8 mmol), (2S)-2-amino-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (2.6 g, 13.8 mmol) and NaHCO3 (3.5 g, 41.4 mmol) in DMSO (70 mL) and H2O (10 mL) were stirred at 95° C. for 15 h. After cooling, the reaction mixture was diluted with H2O (100 mL) and washed with Et2O (100 mL). The H2O layer was acidified to Congo Red midpoint and extracted with Et2O (2×). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to give the titled product (3.59 g, 80%) as a foam. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.89 (2H, m), 3.54 (1H, m), 4.42 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.70 (1H, s), 7.43 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 325.4 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C@:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:27]1)[NH:5][C@@H:6]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:7][N:8](C)[C:9](OCC[Si](C)(C)C)=O)#[N:2].[N+](CC)(CC)(CC)CC.[F-]>CC#N>[C:1]([N:3]=[C:4]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C@:32]([OH:45])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:27]1)[NH:5][C@@H:6]([CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:7][NH:8][CH3:9])#[N:2]
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CNC[C@H](CC1CCCCC1)NC(=NC#N)N1CCC[C@@H]([C@@](O)(CCCCOC)c2ccccc2)C1
Yield: 15.3 %

Procedure:
A solution of (3R)—N′-cyano-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (145 mg, 0.21 mmol) and Et4NF (160 mg, 1.1 mmol) in MeCN (5 mL) was heated at 100° C. in the microwave for 7 min. The reaction mixture was directly submitted to prep HPLC to afford (3R)—N′-cyano-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (16 mg, 14%).