Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[NH:24]1[C:31](=[O:32])[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>C(O)CCCC>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:30]3[C:28](=[O:29])[NH:27][C:25](=[O:26])[NH:24][C:31]3=[O:32])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Nc1nc(N)nc(C=Cc2ccc(C=O)cc2)n1
Reactant: O=C1CC(=O)NC(=O)N1
Agent: O=S(=O)(O)O
Solvent: CCCCCO
Product: Nc1nc(N)nc(C=Cc2ccc(C=C3C(=O)NC(=O)NC3=O)cc2)n1
Temperature: 140 °C
Yield: 88 %

Procedure:
To 7.29 g (30 mmol) of 4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]-benzaldehyde suspended in 150 mL of 1-pentanol at 130° C. was cautiously added 75 mL of hot aqueous sulfuric acid (25 mL of concentrated sulfuric acid was added to 50 mL of water with cautious while stirring). The solid dissolved immediately, and a yellow solution was obtained. To this solution, 4.61 g (36 mmol) of powdered barbituric acid was added while stirring vigorously at 140° C. Yellow precipitate appeared immediately. The mixture was slightly refluxed at 140° C. for 10 min then filtrated while it was hot. Solid washed with 50 mL of warm 1-pentanol, then suspended in 300 mL of water and neutralized with saturated aqueous NaHCO3. The solid was collected by filtration and washed with water. Yield: 9.72 g of yellow product. Yield=88%. 1HNMR (400 MHz, DMSO): δ11.519 (s, 1H), 11.375 (s, 1H), 8.378 (s, 1H), 8.234 (d, J=8.0 Hz, 2H), 7.915 (d, J=16.0 Hz, 1H), 7.857 (d, J=8.0 Hz, 2H), 7.101 (br, 4H), 7.047 (d, J=16.0 Hz, 1H). m.p.>350° C. EA found: C, 52.20; H, 3.86; N, 26.12. Calculated for C16H13N7O3.H2O: C, 52.03; H, 4.09; N, 26.55. MS (rel. abundance): M++1 (68), M++2 (13), 242.1 (5), 217.1 (6), 179.0 (15), 157.0 (30), 101.0 (55), 79.1 (100). MS (high resolution, ES+): MH+(352.1158).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][NH:29][CH3:28])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccc(F)cc2)cc1
Reactant: [BH3-]C#N
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
5-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.49 g) was dissolved in methanol (12 mL), and methylammonium chloride (1.17 g) and sodium cyanoborohydride (0.27 g) were added. After stirring at room temperature for 18 hr, the mixture was concentrated under reduced pressure. The residue was dissolved in water, and the solution was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=5:1) to give the title compound as a colorless solid (yield 0.42 g, 82%).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[CH2:5][C:6](O)=[S:7])#[N:2].[NH2:9][C@H:10]1[CH2:14][O:13][N:12]([C:15]2([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][CH2:18][C:17](=[O:20])[O:16]2)[C:11]1=[O:37]>>[C:1](/[CH:3]=[CH:4]/[CH2:5][C:6]([NH:9][C@H:10]1[CH2:14][O:13][N:12]([C:15]2([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][CH2:18][C:17](=[O:20])[O:16]2)[C:11]1=[O:37])=[S:7])#[N:2]
Reactant: N#C/C=C/CC(O)=S
Reactant: N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O
Product: N#C/C=C/CC(=S)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O

Procedure:
A procedure similar to Example 1 (a), using 143 mg of (E)-2-cyanovinylthioacetic acid and 300 mg of benzhydryl ester of a deacetyl compound of TAN-588, gave 284 mg of benzhydryl 2-((4S)-4-[(E)-2-cyanovinylthioacetamido]-3-oxo-2-isoxazolidinyl]-5-oxo-2-tetrahydrofurancarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:44])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:43])[CH2:34][NH2:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)[nH]1)C(C)C

Procedure:
[1-(2-{5-[4′-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared using method 804 substituting [1-(2-{5-[4′-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C28H33N5O4 calculated 503.3 observed [M+1]+ 504.2; rt=1.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:35](=[O:36])[CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)Cc1ccccc1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and phenylacetyl chloride (23 mg, 150 μmol). Yield 22 mg (80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[C:7]([CH3:21])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:21][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Yield: 90.6 %

Procedure:
To a solution of 2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid methyl ester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1 N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.65 g of the title compound as a white solid, m.p. 171-174° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:20](=O)[C:19]3=[CH:22][C:23](OCCCCC)=[CH:24][CH:25]=[C:18]3[C:17]2=O)=[CH:10][CH:9]=1.Cl>C1COCC1>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][C:19]3[C:18](=[CH:25][CH:24]=[CH:23][C:22]=3[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:17]2)=[CH:10][CH:9]=1
Reactant: CCCCCOc1ccc2c(c1)C(=O)N(CCc1ccc(O)cc1)C2=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCOc1cccc2c1CN(CCc1ccc(O)cc1)C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 188.5 %

Procedure:
A suspension of LAH (40 mg, 1.1 mmol) in THF (1 ml) was added to a solution of N-2-(4-hydroxyphenyl)ethyl-4-pentyloxyphthalimide (208 mg, 0.59 mmol) in THF (1 ml) at 0° C. The mixture was stirred at room temperature for 3.5 hours. This reaction mixture was poured into a 3N aqueous hydrochloric acid solution (20 ml). The mixture was extracted with ethyl acetate (20 ml×3), and washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered of, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=30/1) to give N-2-(4-hydroxyphenyl)ethyl-4-pentyloxyisoindoline (181 mg, 94%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[OH:19])=[C:5]([CH3:7])[N:6]=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[S:3][C:4]([C:8]2[C:17](=[O:18])[NH:16][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[C:9]=2[O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1-c1c(O)c2nccnc2[nH]c1=O
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(Cl)sc1-c1c(OC(=O)C(C)C)c2nccnc2[nH]c1=O

Procedure:
7-(2-Chloro-4-methyl-thiazol-5-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 2.3) (0.30 g), isobutyryl chloride (0.13 ml), and pyridine (0.10 ml) were stirred in dichloromethane (15 ml) at ambient temperature for 2 hours. The reaction mixture was washed successively with aqueous hydrochloric acid (1M), aqueous sodium hydrogen carbonate (saturated) and water. The organic fraction was dried over magnesium sulfate and concentrated to give Compound No. B9 of Table B (0.220 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[Sn]Cl>C(O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[CH:22][CH:23]=1
Reactant: O=C1NCCCC[C@H]1N(Cc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(CN([C@@H]2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
4-Chloro-N-(4-nitro-benzyl)-N-((R)-2-oxo-azepan-3-yl)-benzenesulfonamide (0.10 g, 0.22 mmol) was dissolved in ethanol (15 ml) and treated with SnCl2 (0.42 g, 2.2. mmol) overnight at 70° C. The reaction mixture was concentrated under reduced pressure and purified directly using preparative RP(C18) chromatography: lyophilisate 27 mg; MS: m/e=408.2 (MH+), 425.3 (MNH4+).
Reaction SMILES: [NH2:1][C:2](=[N:34]O)[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[N:26]O)=[C:23]([F:31])[CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>[C].[Pd].C(O)(=O)C>[NH2:34][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([NH2:28])=[NH:26])=[C:23]([F:31])[CH:22]=3)[CH2:13][CH2:12]2)=[CH:32][CH:33]=1
Reactant: NC(=NO)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)c(F)c3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OCCCN2CCC(CCCOc3ccc(C(=N)N)c(F)c3)CC2)cc1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To an acetic acid (2.0 mL) suspension of 56 mg of 4-{3-[1-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-4-piperidinyl]propoxy}-2-fluoro-N′-hydroxybenzamidine was added 0.043 mL of acetic anhydride at room temperature, which was then stirred at the same temperature for one hour. To this mixture was added 5.0 mg of 5% palladium-carbon, which was then stirred under hydrogen atmosphere for 2 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. Thereto were added 6.0 mol/L hydrochloric acid and water, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (silica gel: ODS-AM120-S50 from YMC, eluent; water). The resultant residue was dissolved in 5.0 mL of water, to which a 5.0 mol/L sodium hydroxide aqueous solution was then added to adjust the pH to 12.2. The solution was stirred under cooling with ice for 20 minutes, and the precipitate was collected by filtration to provide 43 mg of 4-{3-[1-(3-{4-[amino(imino)methyl]phenoxy}propyl)-4-piperidinyl]propoxy}-2-fluorobenzamidine as white solid form.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 4-phenoxyphenol (200 mg, 1.07 mmol) m DMF (3 mL) at 0-5° C. was added 60% NaH (75 mg, 1.875 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (382 mg, 1.074 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (256 mg, 64%); MS; m/z 370 (M+H) LCMS (UV)>90%.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][N:3]1CC1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][NH:3]1
Reactant: CC1CCN(Cc2ccccc2)C(C)C1(C)CCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCNC(C)C1(C)CCCO
Yield: 82.4 %

Procedure:
A mixture of 2,3,4-trimethyl-l-(phenylmethyl)-3-piperidinepropanol (45.0 g, 163 mmol), ethanol (200 mL) and 10% palladium on carbon (4.5 g) was placed on a Parr hydrogenator at 50 psi of hydrogen pressure until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was crystallized from ether to afford 24.9 g (82%) of 2.3.4-trimethyl-3-piperidinepropanol. The product was recrystallized from ethyl acetate and had a melting point of 89-91° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=O)=[C:9]([CH:14]=1)[C:10](OC)=[O:11].Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[CH:14]=[C:9]2[C:8]([CH2:15][N:29]([C@H:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[OH:35])[C:10]2=[O:11])=[C:7]([CH3:17])[C:6]=1[CH3:18]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2F)cc2c(c1C)CN([C@H]1CCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A solution of methyl 5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.17 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g), triethylamine (0.06 mL) and anhydrous magnesium sulfate (0.10 g) in THF (3.40 mL) was stirred at room temperature for 10 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.40 mL) and THF (3.40 mL), sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.07 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+].ClCCl>O.CCOCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCCCCCOCCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 2-quinolineethanol (1.00 g), 1,6-dibromohexane (4 ml), TAB (100 mg), 50% aqueous sodium hydroxide (4 ml) and dichloromethane (3 ml) was stirred at room temperature for 40 h, then diluted with water (40 ml) and ether (25 ml). The organic phase was washed with water (20 ml), dried and evaporated in vacuo. The residual oil was purified by FCC eluting with hexane followed by hexane-ether (9:1) and ether, to give the title compound (1.18 g) as a pale yellow oil, t.l.c. (diethyl ether) Rf 0.44.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([CH2:20][OH:21])[N:17]=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([CH:20]=[O:21])[N:17]=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cnc(CO)c2)CC1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cnc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (260 mg) obtained in Step 1 of this Reference Example was dissolved in toluene (10 mL) and methylene chloride (1 mL). To the solution, a solution of sodium bicarbonate (210 mg, 2.50 mmol) in water (8 mL), iodine (370 mg), and 2,2,6,6-tetramethyl-1-piperidinyloxy (15 mg) were added in this order, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, saturated aqueous sodium thiosulfate was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=2/1-1/1) to obtain the title compound (258 mg).
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(=O)N[C@H]2C3C(=CC=CC=3)CCC2)CC2C(=CC(C(O)=O)=CC=2)C1)=O)=O)=O)(C)(C)C.[C:48]([O:52][C:53]([N:55]1[C@H:64]([C:65](=[O:77])[NH:66][C@H:67]2[C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[CH2:70][CH2:69][CH2:68]2)[CH2:63][C:62]2[C:57](=[CH:58][C:59]([O:78][C@@H:79]3[CH2:83][N:82]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@H:81]([C:91]([O:93]C)=[O:92])[CH2:80]3)=[CH:60][CH:61]=2)[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:87]([O:86][C:84]([N:82]1[CH2:83][C@@H:79]([O:78][C:59]2[CH:58]=[C:57]3[C:62]([CH2:63][C@@H:64]([C:65](=[O:77])[NH:66][C@H:67]4[C:76]5[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=5)[CH2:70][CH2:69][CH2:68]4)[N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]3)=[CH:61][CH:60]=2)[CH2:80][C@H:81]1[C:91]([OH:93])=[O:92])=[O:85])([CH3:88])([CH3:89])[CH3:90]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)CN1C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)O
Yield: 96 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound K of Example 1, (2S,4S)-1-tert-butyl 2-methyl 4-(((S)-2-(tert-butoxycarbonyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)pyrrolidine-1,2-dicarboxylate (66 mg, 0.10 mmol) was converted to the title compound (61 mg, 94%). MS (ESI+) m/z 636.3 (M+H)+.
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-tert -butyloxycarbonyl-2-pyrrolidinyl)pyridine (495 mg, 1.5 mmol) was dissolved in toluene (30 mL) and catalytic sodium hydride (10 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture was removed by distillation. The mixture was cooled to 25° C. and water (20 mL) and ethyl acetate (40 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:3) as eluant to afford 5-ethynyl-3-(1-tert -butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil (250 mg, 61%). LRMS (EI) m/e 217 (M+ +H-isobutylene), 216 (M+ -isobutylene); 1 H NMR (CDCl3, 300 MHz): δ8.59 (b-s, 1H), 8.42 (d, J=1.5 Hz, 1H), 7.59 (b-s, 1H), 4.94 (b-m, 0.5H), 4.77 (b-m, 0.5H), 3.64 (b-m, 2H), 3.21 (s, 1H), 2.39 (m, 1H), 1.75-2.0 (b-m, 3H), 1.46 (s, 3H), 1.21 (s, 6H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([N:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][N:41]([CH3:43])[C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1
Reactant: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M198) (397 mg, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (248 mg, 77%).