Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:28])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)CNC(=O)C1COCCN1CC1=C(C(=O)OCC)C(c2ccc(F)cc2Br)N=C(c2nccs2)N1
Yield: 47 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.15 g, 1.1 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.27 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of 4 (50 mg, 37 mmol) according to the method described for the preparation of 5 using (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert.butyl ester instead of 2-amino-pentanoic acid tert.butyl ester provided the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH:17]=[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]3=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)=[O:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:28]1([N:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][N:14]3[CH2:15][CH2:16][C:11]4=[N:10][N:9]([C:6]5[N:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=5)[CH:17]=[C:12]4[CH2:13]3)[CH2:23][CH2:24]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: Cc1ccc(-n2cc3c(n2)CCNC3)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-n2cc3c(n2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-methylpyridazin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine hydrochloride (920 mg, 3.65 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (791 mg, 3.65 mmol), K2CO3 (2.52 g, 18.3 mmol) and KI (66 mg, 0.4 mmol) in CH3CN (20 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×20 mL). The combined extracts are washed with brine (30 mL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. 1H NMR (δ, CDCl3): 8.43 (s, 1H), 8.01 (d, 1H), 7.41 (d. 1H), 3.64-3.67 (m, 6H), 3.40 (s, 2H), 2.88 (s, 4H), 2.66-2.72 (m, 4H), 2.29 (q, 4H), 1.59-2.05 (m, 6H). MS (M+1): 396.2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.CC(C)([O-])C.[K+].[Si:24]([O:31][CH2:32][CH2:33][OH:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[Si:24]([O:31][CH2:32][CH2:33][O:34][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1)([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nnn(-c2cc([N+](=O)[O-])ccc2OCCO[Si](C)(C)C(C)(C)C)c1=O

Procedure:
A similar procedure as detailed below for Compound 133 was used. 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (prepared according to US patent application no. 2011/0130415) (250 mg, 1.1 mmol), potassium tert-butoxide (258 mg, 2.3 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (369 mg, 2.1 mmol) in THF (2 mL) was stirred for 1 hr at room temperature to give the product after workup (yield assumed quantitative=413 mg). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([OH:11])[C@H:9]([CH3:12])[O:8][C:7](=[O:13])[C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][O:4][CH2:3]1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:24][CH:23]([CH3:25])[C:22]([O:1][C@@H:2]1[C@@H:10]([O:11][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:9]([CH3:12])[O:8][C:7](=[O:13])[C@@H:6]([NH:14][C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:5][O:4][CH2:3]1)=[O:26]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](O)[C@H]1O
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (115.0 mg, 0.245 mmol) in pyridine (1.75 mL) was added DMAP (6.40 mg, 0.0520 mmol) followed by isobutyryl chloride (0.10 mL, 0.956 mmol) at 0° C. and the reaction was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with H2O and the reaction was stirred at room temperature for 30 min and then extracted with Et2O. The phases were separated and the aqueous phase was further extracted with Et2O. The combined organic phases were washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless, thick oil (115 mg, 94%): IR (neat) 3353, 2976, 1742, 1519, 1368, 1251, 1155 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.41 (d, J=8.2 Hz, 1H), 5.21-5.12 (m, 1H), 5.12-5.04 (m, 1H), 4.92-4.83 (m, 1H), 4.74 (dd, J=13.4, 6.9 Hz, 1H), 3.95 (dd, J=11.7, 7.0 Hz, 1H), 3.80-3.65 (m, 3H), 2.64-2.41 (m, 2H), 1.44 (s, 9H), 1.32 (d, J=6.2 Hz, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.14 (d, J=7.0 Hz, 3H), 1.10 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.57, 175.47, 171.37, 155.18, 80.34, 74.52, 74.30, 74.15, 73.35, 71.34, 34.01, 33.91, 28.30, 19.01, 18.88, 18.74, 18.71, 18.03; HRMS-ESI (m/z) [M]+ calcd for C21H35NO9, 445.2312; found, 445.2322.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[S-:18][CH2:19][CH3:20].[Na+]>O1CCCC1>[CH2:19]([S:18][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)[CH3:20]
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: CC[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Yield: 67.9 %

Procedure:
Into a round-bottomed flask equipped with a condenser was placed 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.20 g, 0.80 mmol), tetrahydrofuran (6 mL), and sodium thioethoxide (0.10 g, 1.2 mmol). The mixture was heated to reflux for 4 h at which time additional sodium thioethoxide (0.10 g, 1.2 mmol) was added and stirred for 2 additional hours. The reaction mixture was then cooled and poured into ice water and the solids isolated by vacuum filtration to provide 0.15 g (68%) of the product as a white solid. MS (EI) m/z 275.2 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1.[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.O>CN(C=O)C.CCCCCC.CCOC(C)=O>[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](=[O:16])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccncn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccncn1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a suspension of NaH (2.26 g 50%, 47.7 mmol) in DMF (92 mL) under argon atmosphere and cooled to 0° C., 4-methylpyrimidine (3.00 g, 31.9 mmol) was added slowly. Then, ethyl 4-fluorobenzoate (6.40 g, 38.2 mmol) was added and it was stirred at room temperature overnight. Water was added and the solvent was evaporated. The residue was taken up in a mixture of EtOAc and brine. The phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 3.30 g of the desired compound (yield: 48%).
Reaction SMILES: [C:1]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[C:1]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:22]([O:30][CH2:31][CH3:32])=[O:29])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 2-(1-tridecynyl)benzaldehyde (6.42, 22.6 mmol from example 3) was condensed with diethyl malonate (3.72 g) as described in example 1 to give 2.00 g (21%, 36% on the basis of unrecovered starting material) of the title compound identical with that prepared in example 6 above.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([O:8][CH2:9][C@@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)CO[Si](C)(C)C(C)(C)C
Yield: 95.1 %

Procedure:
A procedure similar to that described in Preparation 9 was repeated, except that 10.22 g of benzyl N-[2-t-butyldimethylsilyloxy-1(S)-methylethyl]carbamate (prepared as described in Preparation 32), 2.00 g of 10% w/w palladium-on-carbon and 80 ml of ethanol were used, to give 5.69 g of the title compound having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+9.7° (methanol, c=1.040).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]1[C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[O:31]1[C:35]2([CH2:40][CH2:39][C:38](=[CH:20][C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(C=C1CCC2(CC1)OCCO2)OCc1ccccc1
Temperature: 95 °C
Reaction time: 48 h
Yield: 92.1 %

Procedure:
Benzyl (triphenylphosphoranylidene)acetate (47.30 g, 115.2 mmol) was added to a solution of 1,4-dioxaspiro[4,5]decan-8-one (10.0 g, 64.02 mmol) in toluene (300 ml) at room temperature, and the mixture was stirred at 95° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was diluted with ether and hexane, the resultant precipitate was removed by filtration, and the filtrate was concentrated. The residue was chromatographed on silica gel column (hexane:ethyl acetate=9:1) to give the title compound as a colorless oil (17.0 g, yield 92%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:24][CH2:23]3)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3cc(-c4ccc(Cl)cc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.5 %

Procedure:
A suspension of 1.69 g (0.0087 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 95 ml of dimethylformamide was treated with 2.035 g (0.00726 mol) of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.35 ml (0.0;24 mol) of triethylamine and stirred at room temperature under argon for 66 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 16 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent and digested in diethyl ether. 2.0 g (63%) of 5-[6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as a white solid. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 205°-208°.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([F:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1>[Pd].CO>[C:19]([O:18][C:16]([N:11]1[CH2:12][C@@H:13]([F:15])[CH2:14][C@H:10]1[C:9]([OH:23])=[O:8])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Methanol (95 mL) was carefully added to a mixture of 11 (2.8 g, 8.7 mmol) and palladium on carbon (10% w/w, 1.0 g, 0.94 mmol Pd) under Ar(g). A balloon filled with H2(g) was affixed to the reaction flask, and the mixture was stirred overnight. After 24 h, unreacted starting material remained, so an additional 0.95 g (0.89 mmol Pd) of Pd/C were added and a fresh balloon filled with H2(g) was placed on the flask. After stirring overnight, TLC indicated reaction had gone to completion, and the mixture was filtered through Celite. The filtrate was concentrated to a white solid by rotary evaporation under reduced pressure and dried under vacuum, affording 12 (1.8 g, 7.6 mmol, 87%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:21]([C:20]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:19]=4[O:18][CH3:17])=[O:22])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Product: COc1cc(C)ccc1C(=O)N1CC2CN(c3nc(C)cc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 23 and 2-methoxy-4-methylbenzoic acid. MS (ESI): mass calculated for C21H26N4O2, 366.21; m/z found 367.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.13 (d, J=7.6, 1H), 6.77 (d, J=7.6, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 4.00-3.40 (m, 11H), 3.27-2.85 (m, 3H), 2.41-2.19 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[F:8].[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[OH:19])=[O:18]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1F)CCC

Procedure:
N-(3-(3-Bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol following the method used in Example 7 to give 2,2,2-trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide as a pale yellow oil. Yield (1.37 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.18 (t, J=9.0 Hz, 1H), 5.41 (d, J=4.8 Hz, 1H), 5.19 (s, 1H), 4.58-4.54 (m, 1H), 3.28-3.16 (m, 2H), 1.82-1.69 (m, 2H), 1.63-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:14]([CH3:13])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: CNCCc1ccccn1
Reactant: COc1ccc2c(Cl)noc2c1
Product: COc1ccc2c(N(C)CCc3ccccn3)noc2c1
Temperature: 140 °C

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (2.5 g) and 2-(2-methylaminoethyl)pyridine (11.0 g). The reaction was heated to 140° C. over 72 hours and then cooled to room temperature. The residue was partitioned between EtOAc and brine, washed with brine (4×), and the organic phase was dried over MgSO4 and concentrated in vacuo. Preparative liquid chromatography (silica gel) eluting with 5% acetone/CH2Cl2 provided a residue upon evaporation (1.5 g) which was dissolved in ether and made acidic with ethereal hydrochloric acid. The precipatate was dried in vacuo and recrystallized from ethanol to yield 0.9 g, m.p. 152-153° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br-:15].[NH2:16][C:17]1[CH:42]=[C:41]([C:43]([O:45][CH3:46])=[O:44])[CH:40]=[CH:39][C:18]=1[CH2:19][P+:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[Br-:15].[CH3:46][O:45][C:43]([C:41]1[CH:40]=[CH:39][C:18]([CH2:19][P+:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([NH:16][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:42]=1)=[O:44]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(N)c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Nc1cc(C(=O)OC)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 73.5 %

Procedure:
n-Dodecanoyl chloride (9.9 g) was added dropwise to a stirred suspension of (2-amino-4-methoxycarbonylbenzyl)triphenylphosphonium bromide (22.9 g) in dry dimethylformamide (225 ml) and stirring continued for 3 hours. The resulting solution was evaporated in vacuo to give an orangebrown oil which on treatment with water gave a solid. The solid was collected, washed with water, dried, washed with diethyl ether and collected to give [4-methoxycarbonyl-2-(n-dodecanamido)benzyl]triphenylphosphonium bromide (22.9 g) in the form of a pale yellow solid, m.p. 142°-145° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][OH:32])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: NCCOCCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCOCCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 10 ml of 2-(2-aminoethoxy)ethanol are stirred at room temperature for 2 h. The mixture is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-[2-(2-hydroxy-ethoxy)ethyl]acetamide remains as colorless crystals of m.p. 173-174° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)=[O:6])#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[CH2:34][CH:35]([CH3:36])[CH3:37])#[N:2]
Reactant: CC(C)CC(Cc1ccccc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(Cc1ccccc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N

Procedure:
To tert-butyl 4-[2′-(2-{[(cyanomethyl)amino]carbonyl}-4-methylpentyl)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate (407 mg, 0.808 mmol) in dry THF (10 mL) under dry nitrogen was gradually added a total of 6.5 equivalents of MeSO3H (total of 340 μL, 5.25 mmol) over a period of 3 days in portions of 1–2 equivalents at a time. Aqueous sat. NaHCO3 was added carefully and the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (NH4/OH/MeOH/CH2Cl2, 1/9/90) to afford N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-2-yl]methyl}pentanamide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][C:7]=1[CH3:8])=O.Cl.[NH2:15]O>CCO.CN(C=O)C.O=S(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][C:7]=1[CH3:8])#[N:15]
Reactant: CCOC(=O)c1cc(C=O)c(C)[nH]1
Reactant: NO
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cc(C#N)c(C)[nH]1

Procedure:
Ethyl 4-formyl-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 15, 0.2 g, 1.1 mmol) and hydroxylamine hydrochloride (0.08 g, 1.1 mmol) were dissolved in EtOH (10 ml) and refluxed for 1.5 hours. The mixture was concentrated under vacuum to give yellow solid, which was dissolved in DMF (5 ml) before addition of SOCl2 (0.35 ml) at 0° C. The solvent was removed under vacuum after the completion of the reaction and the residue was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic extracts were dried over MgSO4 and concentrated to give brown solid (0.16 g, crude).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OC)=[O:4].C[O-].[Na+].O1CCCC1.[H][H]>C(OCC)C>[CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](CO)Cc1ccccc1
Yield: 85.9 %

Procedure:
Methyl (S)-2-methyl-3-phenylpropionate (5 mmol, 78.4% ee), a dichlororuthenium complex 8 (0.05 mmol), sodium methoxide (5 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 80° C. for 16 hours. The reaction solution was diluted with 20 mL of diethyl ether, and was passed through 8.9 g of silica gel. The silica gel was washed with diethyl ether. The solution thus obtained was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 13.4 g, hexane/ethyl acetate=8/1). Thus, (S)-2-methyl-3-phenylpropanol (645 mg, 18.4% ee) was obtained.