Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]1)(=[O:20])=[O:19])[CH:12]=[CH:11]2.C[I:42]>CO>[I-:42].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][N+:37]([CH3:1])=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[O:40])[CH2:23][CH2:22]1)(=[O:20])=[O:19])[CH:12]=[CH:11]2
Reactant: c1ccccc1
Reactant: CI
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: CO
Product: C[n+]1ccc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cc1
Product: [I-]
Yield: 58 %

Procedure:
In a mixed solvent of benzene (10 ml) and methanol (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (300 mg) obtained in Example A-1 was dissolved at room temperature, followed by the addition of methyl iodide (1 ml). To the resulting mixture, the same amount of methyl iodide was added three times at intervals of 24 hours, followed by heating under reflux for 4 days. The reaction mixture was distilled under reduced pressure and the residue was washed with methanol, collected by filtration and dried, whereby the title compound (229 mg, 58%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([OH:25])[CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([OH:25])[CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=C1CCc2cc(OCC(O)CSc3ccc(Cl)c(Cl)c3)ccc2N1
Product: O=C1CCc2cc(OCC(O)CS(=O)c3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
The 6-[3-(3,4-dichlorophenyl-mercapto)-2-hydroxy-propoxy]-3,4-dihydro-carbostyril thus obtained, was oxidized analogous to Example 123 with hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[C:12]1[C:13](=[O:32])[N:14]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:15]=[C:16]([C:19]2([CH3:24])[O:23][CH2:22][CH2:21][O:20]2)[C:17]=1[CH3:18].O>CN(C)C=O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:14]2[C:13](=[O:32])[C:12]([O:10][CH2:9][C:5]3[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=3)=[C:17]([CH3:18])[C:16]([C:19]3([CH3:24])[O:23][CH2:22][CH2:21][O:20]3)=[N:15]2)=[CH:30][CH:29]=1
Reactant: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 62.5% sodium hydride (92 mg) in N,N-dimethylformamide (8 ml) was added 3-pyridylcarbinol (0.25 ml) under ice cooling, followed by stirring at room temperature for 20 minutes. Then, 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (738 mg) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was crystallized from ether to obtain 2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-4-(3-pyridylmethoxy)-3(2H)-pyridazinone (320 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 9, 0.5 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.35 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.45 g of desired product. MS (electrospray): 384 (M+1) for C18H18FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.60 (s, 1H) 8.20 (m, 1H) 8.15 (m, 1H) 7.60 (m, 1H) 7.40 (s, 1H) 6.30 (d, 1H) 6.20 (s, 1H) 5.35 (m, 1H), 1.90 (m, 1H) 1.60 (d, 3H) 1.00 (m, 2H) 0.80 (m, 2H).
Reaction SMILES: [N:1]([C:4]1([CH2:20][C:21](OCC)=[O:22])[C:17]2[CH:16]=[C:15]([Cl:18])[N:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][C:7]([Br:19])=[CH:8][CH:9]=2)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:4]1([CH2:20][CH2:21][OH:22])[C:17]2[CH:16]=[C:15]([Cl:18])[N:14]=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][C:7]([Br:19])=[CH:8][CH:9]=2
Reactant: CCOC(=O)CC1(N=[N+]=[N-])c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
A solution of ethyl 2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.82 g, 96 mmol) in THF (400 ml) was cooled to 0° C. under nitrogen atmosphere. A solution of LAH (1.0M solution in THF; 116 ml, 116 mmol) was added drop wise at 0° C. over a time period of 90 minutes. Upon complete addition, the reaction mixture was warmed to RT and stirred for additional 10 minutes. The reaction mixture was quenched with sodium sulfate decahydrate (50 g) and stirred for 20 minutes at RT. Celite was added to the reaction mixture and the suspension was filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by chromatography [1-2% (2M ammonia in MeOH)/DCM] to afford 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (17.3 g, 48.6 mmol, 50.5% yield).
Reaction SMILES: [C:1](=[O:18])([O:10]CC1C=CC=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][N:20]([CH3:22])[CH3:21].O>CO>[C:1](=[O:2])([O-:18])[OH:10].[CH3:19][N+:20]([CH3:22])([CH3:21])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)OCc1ccccc1
Reactant: CN(C)C
Solvent: O
Solvent: CO
Product: C[N+](C)(C)Cc1ccccc1
Product: O=C([O-])O
Reaction time: 5 h

Procedure:
101.6 g of dibenzyl carbonate, 23.6 g of trimethylamine, 60.5 g of water and 20.0 g of methanol were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 150° C., the reaction was continued for 5 hours at 150° C. Trimethylbenzylammonium hydrogencarbonate was obtained in a yield of 81.0 mol % (based on trimethylamine).
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:28]=[CH:27][C:11]([O:12][C@@H:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1.O>C(O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:9]=[CH:10][C:11]([O:12][C@@H:13]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]([OH:16])=[O:15])=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
21.5 mmol of potassium hydroxide are added to a solution of 4.3 mmol of ethyl (2S)-2-(4-furan-2-ylphenoxy)-4-phenylbutanoate, obtained in the preceding example, in 30 ml of ethanol. The mixture is refluxed for 30 minutes, 15 ml of water are added and refluxing is continued for 3 hours 30 minutes. After cooling to room temperature, the ethanol is evaporated off under vacuum. The product is taken up in water and washed with ether. The aqueous phase is acidified with 10% hydrochloric acid. A white precipitate forms, which is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated under vacuum. 1.2 g of a beige-coloured solid, that recrystallizes from a hexane/ethyl acetate mixture to give 1 g of a solid melting at 140-142° C., are obtained.
Reaction SMILES: O1CCCC[CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[CH2:14](O)[CH2:15][C:16]#C.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.N1C=CC=CC=1.O1C=CCCC1>C(Cl)Cl.O>[OH:9][CH2:10][CH2:11]/[C:12](/[CH:15]([CH3:16])[CH3:14])=[CH:13]\[C:8]([O:7][CH3:2])=[O:26]
Reactant: C#CCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCC(OC2CCCCO2)OC1
Agent: C1=COCCC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C(\CCO)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate was synthesized according to scheme shown in FIG. 1. Unless otherwise specified all reagents and solvents were purchased from Aldrich Chemical Co. Tetrahydropyranyl ether (THP) protection of 3-butyn-1-ol was conducted following a procedure by Rama Rao et al. (1986). A solution of 3-butyn-1-ol (approximately 14.0 g, approximately 0.2 mol) in methylene chloride (approximately 75 ml, dried by distillation from CaH2) was placed in a flask under N2. The mixture was cooled to approximately 0° C., and pyridine p-toluenesulfonate (approximately 0.28 g) was added. 3,4-Dihydro-2H-pyran (about 20.1 ml) was added via a dropping funnel maintaining the temperature between approximately 0 and approximately 5° C. The mixture was stirred at this temperature for about 1 h, then warmed to about 25° C. and stirred for additional about 2 h. Thin layer chromatography (silica gel, hexanes/ethyl acetate, approximately 3:1) showed that the reaction was complete. The reaction mixture was taken into cold water (approximately 70 ml) and transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with methylene chloride. Combined organic extracts were washed with NaHCO3 (aq), brine, and dried with Na2SO4 (anhydrous). Distillation produced approximately 23 g of THPO-protected 3-butyn-1-ol with a by of about 50-55° C./4 mm Hg with GC-MS (m/z, relative intensity): 153 (2, M+-1), 99 (9), 85 (100), 79 (9), 67 (20), 53 (42), 41 (33). The mass spectrum matched the spectrum presented in the NIST MS library for this intermediate compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[I-].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (300 mg, 1.39 mmol) was dissolved in N,N-dimethylformamide (5 mL). While this solution was chilled in an ice bath, 60% sodium hydride in oil (83.6 mg, 2.09 mmol) was added. The reaction mixture was stirred for 10 min while ice-chilled and for another 10 min at room temperature. 2-chlorobenzothiazole (0.344 mL, 2.78 mmol) and sodium iodide (208 mg, 1.39 mmol) were then added and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine. The washed product was then dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 460 mg (95%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.C(#N)C.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:34])[CH:32]=[CH2:33].[CH2:35](OCC1OC1)[CH:36]1[O:38][CH2:37]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CC(N(C)C)=O>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][C:19]([O:21][CH2:35][CH:36]([OH:38])[CH2:37][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31](=[O:34])[CH:32]=[CH2:33])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(F)c2c(=O)c3ccccc3sc12
Reactant: C(OCC1CO1)C1CO1
Reactant: C=CC(=O)OCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Br-]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: C=CC(=O)OCCCCOCC(O)COC(=O)COc1ccc(F)c2c(=O)c3ccccc3sc12
Temperature: 94 °C
Yield: 114.3 %

Procedure:
A reaction mixture containing (1-fluoro-9-oxo-9H-thioxanthen-4-yloxy)-acetic acid (4.0 g, 13 mmol), acetonitrile (65 mL), dimethylacetamide (30 ml), tetrabutylammonium bromide (0.4 g, 1.3 mol), 2,6-di-tert-butyl-4-methylphenol (0.03 g, 0.00013 mol) and 4-hydroxybutylacrylate glycidylether (2.6 g, 13 mmol) was heated to reflux (94° C.). The mixture was allowed to stir at reflux temperature for 24 hours. The solvent was removed under reduced pressure. The residual oil was dissolved in dichloromethane (100 mL) and extracted with a mixture of distilled water (50 ml) and an aqueous solution of sodium hydroxide 1N (50 mL). The organic layer was isolated and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded 7.5 g of the crude acrylic acid 4-{3-[2-(1-fluoro-9-oxo-9H-thioxanthen-4-yloxy)-acetoxy]-2-hydroxy-propoxy}-butyl ester. The product was purified on a Merck Super Vario Prep Column using dichloromethane/ethyl acetate (75/25) as eluent, yielding 2.8 g of 4-{3-[2-(1-fluoro-9-oxo-9H-thioxanthen-4-yloxy)-acetoxy]-2-hydroxy-propoxy}-butyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[NH:7][C:6]=2[CH:20]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC1C=CC2N=C(C(N)C)N(C3C=CC=CN=3)C=2C=1>CCOC(C)=O.CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:8]([CH:10]([NH2:12])[CH3:11])=[N:7][C:6]=2[CH:20]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2[nH]1
Reactant: Fc1ccccn1
Agent: CC(N)c1nc2ccc(F)cc2n1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(N)c1nc2cc(F)ccc2n1-c1ccccn1
Temperature: 150 °C
Reaction time: 0.23 h
Yield: 31.6 %

Procedure:
To a microwave vial was added (S)-tert-butyl 1-(6-fluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate (Prepared in Example 16, 0.5126 g, 1.835 mmol), N,N-Dimethylacetamide (4.08 mL), 2-fluoropyridine (0.189 mL, 2.202 mmol), and cesium carbonate (1.196 g, 3.67 mmol). The mixture was heated for 40 min in the microwave reactor (Temperature: 150° C. Pressure: 92˜94 psi, Power: 8˜10 W). At this time, the mixture was poured into EtOAc (100 mL), filtered and then concentrated on the high vacuum to remove most of the DMA. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 20% gradient of EtOAc in hexane over 14 min, then 20% EtOAc in hexane for 14 min, then 20 to 50% gradient of EtOAc in hexane over 14 min, and then 50% EtOAc in hexane for 14 min as eluent to give a mixture of four isomer of two regioisomers and two stereoisomer of each regioisomer, 1-(6-fluoro-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)ethanamine and 1-(5-fluoro-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.1486 g, 0.580 mmol, 31.6% yield) as a yellow syrup: LC-MS (ESI) m/z 257.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccccc2)c1O

Procedure:
A mixture of 6.69 g (24.7 mmol) of 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone, from the preceding example, 5.35 g (31.3 mmol) of benzyl bromide, 14.9 g (0.108 mol)of anhydrous potassium carbonate, 115 mL of dry N,N-dimethylformamide, and 230 mL of acetone was stirred and refluxed for 8 hr. After being cooled, the slurry was filtered with suction and the solids washed well with acetone. The filtrate and washes were combined and concentrated under reduced pressure to give a yellow oil which was chromatographed on silica gel. There was obtained 5.57 g (62.6%) of the desired monoether as a pale-yellow solid. Recrystallization of a sample from hexane-ethyl acetate gave the title compound as colorless needles, mp 115°-116° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>FC(F)(F)C(O)=O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(=O)n(C2CCCCC2)n1C
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])c(=O)n(C2CCCCC2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To trifluoroacetic acid (1940 mL) cooled to −15° C. was added 2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (535 g, 2231 mmol) and the reaction mixture was allowed to warm to 0° C. Nitric acid 90% (211 mL, 4461 mmol) was added dropwise over 90 minutes maintaining the temperature below 15° C. and the resulting mixture was stirred for 30 minutes at 10° C. The product mixture was slowly poured into ice water (8 L) and stirred for 30 minutes. The solid was collected by filtration and washed with water (2×2 L), saturated sodium bicarbonate solution (1×2 L), water (2×2 L), TBME (3×2 L) and heptane (2×2 L). The solid was dried in the vacuum oven to yield the title compound as a beige powder.
Reaction SMILES: [H][H].[C:3](#N)[CH2:4][CH3:5].C(N)CC.[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>[C-]#[W]>[CH2:11]([N:14]([CH2:3][CH2:4][CH3:5])[CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]
Reactant: CCC#N
Reactant: [H][H]
Reactant: CCCNCCC
Agent: [C-]#[W]
Solvent: CCCN
Product: CCCN(CCC)CCC

Procedure:
Hydrogen (10 ml/min) was passed through a saturator filled with propionitrile at 24° C., and the mixture was passed over the tungsten carbide catalyst at 150°-300° C. The catalyst that was prepared in Example 1 had been pretreated at 550° C. with hydrogen for fifteen hours. A mixture of propylamine, dipropylamine and tripropylamine was formed in the reactor, according to GC analysis. At temperatures above 250° C. formation of propane was also observed.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:38]([O:42][C:43](=[O:49])[C@H:44]([CH3:48])[C@@H:45]([NH2:47])[CH3:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:38]([O:42][C:43](=[O:49])[C@H:44]([CH3:48])[C@@H:45]([NH:47][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH3:46])([CH3:39])([CH3:41])[CH3:40]
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: C[C@H](N)[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
A flask was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid (40 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol) and CH2Cl2 (2 mL). EDC (35 mg, 0.18 mmol) was added, and the mixture was stirred for 10 min. (2R,3S)-3-Amino-2-methyl-butyric acid tert-butyl ester (22 mg, 0.13 mmol) and Hunig's base (0.050 mL, 0.26 mmol) were then added, and the resulting mixture was stirred for 3 days at r.t. Hydrochloric acid (0.1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-10% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound as a white solid. MS: (−) m/z 460.31 (M−1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CNCc1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a suspension of 11.0 g of glycine ethyl ester hydrochloride in 100 mL of dimethylformamide at 25° was added 22.0 mL of triethylamine. To the resulting milky suspension was added 9.08 g of 4-benzyloxybenzyl chloride in 50 mL of DMF dropwise over 0.5 hour. The mixture was stirred for 16 hours at 25°. The reaction mixture was diluted with diethyl ether and then filtered to remove the precipitated triethylamine hydrochloride. The resulting solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Kugelrohr distillation provided 5.90 g of N-(4-benzyloxybenzyl)glycine ethyl ester [bp 160°-180° (0.015 torr.)]; NMR (200 MHz, CDCl3): δ 7.43-7.27 (m, 5H); 7.06 (A2B2, 4H); 5.01 (s, 2H); 4.14 (quart., 2H); 3.71 (s, 2H); 3.36 (s, 3H); 2.01 (bs, 1h); 1.24 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(OC([NH:43][CH:44]([CH2:50][CH:51]([CH3:53])[CH3:52])[C:45]([O:47][CH2:48]Cl)=[O:46])=O)(C)(C)C>CN(C=O)C>[ClH:1].[NH2:43][C@@H:44]([CH2:50][CH:51]([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)=[O:46]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)[C@@H](N)CC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Product: Cl
Yield: 140.5 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in DMF (2.5 mL), KOH (69 mg, 1.22 mmol), and a solution of chloromethyl 2-((tert-butoxy-carbonyl)amino)-4-methylpentanoate (179 mg, 0.61 mmol) in DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (287 mg, 62.8%). The title compound was characterized by LC-MS and 1H NMR as shown below: