Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl.O>O1CCCC1>[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2I)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2ccccc2I)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride (1.17 g, 29.25 mmol, 60% in oil) in anhydrous tetrahydrofuran (40 mL), which had been cooled to 0° C., was added N-(2-iodophenyl)-4-methoxybenzenesulfonamide (9.36 g, 19.6 mmol) in tetrahydrofuran (20 mL). After the addition was complete, the cooling bath was removed and the mixture stirred at room temperature for 90 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (4.25 g, 25.5 mmol) in tetrahydrofuran (20mL) was added dropwise and the reaction mixture stirred for an additional 16 hours. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated, aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate was evaporated in vacuo to yield the crude title compound as a colorless oil. Purification by silica gel chromatography by elution with hexane-ethyl acetate (10:1) provided the title compound as a colorless oil. Trituration with hexane provided the title compound as a white solid (8.55 g, 16.5 mmol, 84%), m.p. 69-70° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[CH2:31][CH2:30][N:29]2[C:24](=NCCC2)[CH2:23][CH2:22]1.C1(C=CC#N)CC1.O>CN(C=O)C>[CH:21]1([CH:22]([N:15]2[CH:14]=[C:13]([C:11]3[N:10]4[CH:18]=[CH:19][N:20]=[C:9]4[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:12]=3)[CH:17]=[N:16]2)[CH2:23][C:24]#[N:29])[CH2:31][CH2:30]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CC=CC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation; K-1; 0.130 g, 0.490 mmol) in dry DMF (2 mL) was added DBU (89.5 mg, 0.588 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.183 g, 1.96 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Additional 3-cyclopropylacrylonitrile (0.046 g, 0.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was added to H2O (8 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO4/activated carbon. The solution was eluted through a short SiO2 column (15 mL course frit funnel, ½ full of SiO2) eluting first with EtOAc, then with 10% MeOH/EtOAc. The 10% MeOH/EtOAc fraction was concentrated and the resulting residue treated with Et2O and sonicated to give a granular suspension. The precipitate was allowed to settle, Et2O decanted off, solid washed with Et2O and then dried under vacuum to provide a 3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (40 mg, 23% yield) as a white powder. MS (apci) m/z=359.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([Cl:40])[CH:32]=5)[O:28][N:27]=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[C:33]([Cl:40])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3ccn4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)(CO)CO)no2)cc1Cl
Yield: 83.3 %

Procedure:
When the product of Step D was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 83.3% yield, as off white solid. 1H-NMR (DMSO-d6) 1.46 (tr, 3H, J=6.85 Hz); 2.99-3.44 (m, 4H); 3.52 (tr, 2H, J=8.96 Hz); 3.71 (tr, 4H, J=10.46 Hz); 4.15 (q, 2H, J=6.97, 13.97 Hz); 6.77 (d, 1H, J=8.12 Hz); 6.99 (d, 1H, J=8.65 Hz); 7.17 (tr, 2H, J=7.74 Hz); 7.45 (d, 1H, J=8.68 Hz); 7.98 (d, 1H, J=8.75 Hz); 8.14, (broad s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[O:27][CH3:28])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[F:36]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:15]([N:40]1[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][C:35]([F:36])=[C:30]([F:29])[CH:31]=3)[CH2:42][CH2:41]1)[N:16]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: Fc1ccc(N2CCNCC2)cc1F
Reactant: COC(=O)/C=C/c1cccc(F)c1N=C=Nc1cc(C(F)(F)F)ccc1OC
Solvent: ClCCl
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)c(F)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
700 mg (1.78 mmol) of methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]-imino}methylene)amino]phenyl}-2-propenoate (Example 18A), 352 mg (1.78 mmol) of 1-(3,4-difluorophenyl)piperazine (Example 16A) and a spatula tip of silica gel are stirred in 20 ml of dichloromethane at room temperature for 1 hour and then under reflux for 20 hours. The target compound is then purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10:1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([N:14]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH3:3])[C:15]1=[O:16])[CH3:19]
Reactant: CCI
Reactant: CSc1ncc2cc(C)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(C)cc2cnc(SC)nc21
Temperature: 50 °C
Yield: 78.2 %

Procedure:
To a suspension of NaH (261 mg of a 60% suspension of NaH in mineral oil) in 40 mL of dimethylformamide was added 6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (926 mg, 4.48 mmol). The reaction mixture was heated to 50° C. resulting in a clear solution. The solution was cooled slightly, and iodoethane (491 μL, 6.14 mmol) was added. The reaction was heated at 50° C. for 10 minutes, then cooled to room temperature and partitioned between ice water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was partitioned between hexane and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Hexane was added and the resultant solid collected by filtration to provide 824 mg (78%) of 8-ethyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 84-86° C.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:30][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:31](Cl)(=O)[CH2:32][CH2:33][CH3:34]>>[CH3:29][S:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][CH:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:31]([CH2:32][CH2:33][CH3:34])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:30][C:14]3=[CH:15][N:16]=2)=[CH:20][CH:21]=1)(=[O:28])=[O:27]
Reactant: CCCC(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1
Product: CCCc1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from N-hydroxy-4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.52 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1cccnc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cccnc3)c21
Yield: 45.9 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a pale yellow powder in 45.9% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 3-pyridinemethanol.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([S:10][CH2:11][C:12]([O:14][C:15]([CH3:18])(C)C)=[O:13])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[O:3].N[C:20]1C=C(SC(C)C(OCC)=O)C=CC=1.ClC(OC(Cl)(Cl)Cl)=O>>[N:1]([C:4]1[CH:5]=[C:6]([S:10][CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:18])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[C:2]=[O:3]
Reactant: CC(C)(C)OC(=O)CSc1cccc(N=C=O)c1
Reactant: CCOC(=O)C(C)Sc1cccc(N)c1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)Sc1cccc(N=C=O)c1

Procedure:
Ethyl 2-(3-isocyanatophenylthio)propionate can be obtained in a manner analogous to that described in Example 1 for the preparation of tert-butyl (3-isocyanatophenylthio)acetate, but starting for 1 g of ethyl 2-(3-aminophenylthio)propionate, 0.54 cm3 of trichloromethyl chloroformate and 0.09 g of carbon. 1.18 g of ethyl 2-(3-isocyanatophenylthio)propionate are thus obtained in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([NH:25][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and dodecylamine comparable as in Example A.
Reaction SMILES: [OH:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:8](=[O:27])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:38]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:39]=[CH:40][C:41]([C:44]([O:1][C:2]2[CH:37]=[CH:36][C:5]([CH2:6][N:7]([CH2:28][C:29]([OH:31])=[O:30])[C:8](=[O:27])[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:26])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)=[CH:4][CH:3]=2)=[O:45])=[CH:42][CH:43]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Reaction time: 18 h
Yield: 25 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL) were added [1,1′-biphenyl]-4-carbonyl chloride (26 mg, 0.119 mmol). The reaction was stirred for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 12.5 mg (25%) of 2-(N-(4-(([1,1′-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 32. LCMS-ESI (m/z) calculated for C38H32N2O7: 629; found 628 [M−H]−, tR=7.83 min (Method 4). NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.21 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.4 Hz, 3H), 7.79 (d, J=7.7 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.58-7.41 (m, 4H), 7.41-7.17 (m, 6H), 6.88 (d, J=8.2 Hz, 2H), 4.64 (d, J=36.7 Hz, 2H), 3.95 (d, J=33.6 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 2H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].CI.CN(C=O)C.[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:37]3[CH:42]=[CH:41][C:40](O)=[C:39]([F:44])[CH:38]=3)[CH2:26][C@H:25]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[O:28])=[CH:17][N:16]=1>O>[CH3:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@:24]2([C:37]3[CH:42]=[CH:41][C:40]([O:4][CH3:1])=[C:39]([F:44])[CH:38]=3)[CH2:26][C@H:25]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[O:28])=[CH:17][N:16]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ncc(OC[C@@]2(c3ccc(O)c(F)c3)C[C@H]2C(=O)Nc2ccc(F)cn2)c(C)n1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([C@]2(COc3cnc(C)nc3C)C[C@H]2C(=O)Nc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
Cesium carbonate (172 mg) and methyl iodide (26.8 ul) were added to a DMF (5 ml) solution of the compound 321 (150 mg), and the obtained mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 2:3), so as to obtain the title compound (70 mg).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[C:7]1=[O:12])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1>>[CH3:2][O:3][C:4]([C:6]1([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[C:7]1=[O:12])=[O:5]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCC(C)C1=O
Agent: [Na]
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O

Procedure:
The obtained sodium salt of 3-methyl-2-oxocyclopentanecarboxylic acid methyl ester is reacted with (4-chlorophenyl)methyl chloride to produce 1-[(4-chlorophenyl)methyl]-3-methyl-2-oxocyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 6-(1-phenoxyethyl)nicotinate (400 mg, 1.55 mmol) in tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was added lithium hydroxide (377 mg, 15.7 mmol). The resultant reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure and was treated with aqueous 1N hydrochloric acid (5 mL). Then the mixture was concentrated and the residue was purified by prep-thin layer chromatography to give 6-(1-phenoxyethyl)nicotinic acid (350 mg, 92.5%) as a white solid. LRMS (M+H+) m/z: calcd 244.09. found 244 1H NMR (300 MHz, DMSO) δ 9.08 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.1 Hz, J2=2.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.19 (m, 2H), 6.87 (m, 3H), 5.49 (s, 1H), 1.66 (d, J=6.6 Hz, 3H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@@H]([C@H]([C@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
It is also known that both D-glucose and D-mannose can be epimerized in an aqueous solution containing about 17% by weight of D-glucose or D-mannose, based on total solution weight (i.e., 20% by weight of glucose, based on the weight of water) and a small amount of molybdic acid catalyst producing a solution containing 25 percent D-mannose, remainder D-glucose on the dry basis. This epimerization is described by V. Bilik, Chem. Zvesti, 26, 183-186 (1972) and in Czech patent 149,051 (June 15, 1973). No reaction took place when sodium molybdate was used as the catalyst. Bilik and co-workers have also found that various other sugars can be epimerized in the presence of molybdate ions in aqueous solution. For example, D-fructose gives a mixture of D-sorbose, D-tagatose, and D-psicose, and sucrose gives a mixture of D-mannose and D-sorbose in a similar reaction. [Chemical Abstracts, 80, 146433s (1974)]. Also, L-arabinose gives a mixture of L-arabinose and L-ribose [Czechoslovakian Patent 149,472, July 15, 1973; C.A. 81, 78189k (1974)]; L-mannose gives a mixture of L-glucose and L-mannose [C.A. 81, 91887f (1974)]; and D-galactose gives a mixture of D-talose and D-gulose in addition to D-galactose [C.A. 81, 152523h (1974)].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.O.[C:28](OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH2:28])=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:25])[CH3:26]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Product: C=CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and methyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 4 H), 5.73 (m, 1H) 4.81 (dd, J=4.8, 1.8 Hz, 2 H), 4.35 (s, 2 H), 3.43 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J =6.6 Hz, 1 H), 3.07 (d, J=1.8 Hz, 2 H), 1.24 (m, 13 H). FAB-MS: calcd for (C21H26FNO) 327, found 328 (M+H). Anal. Calcd for C21H26FNO: C, 74.17; H, 7.71; N, 4.12; F, 5.59+0.7 H2O. Found: C, 74.17; H, 7.57; N, 3.94; F, 5.26. mp 69-71° C. Rf=0.35 (15% ethyl acetate/hexane).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(C(C)C)CC)(C)C.[CH2:25]([O:28][C:29](Cl)=[O:30])[CH:26]=[CH2:27].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:6][C:29]([O:28][CH2:25][CH:26]=[CH2:27])=[O:30])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of L-Tyrosine methyl ester hydrochloride (25 g, 107.9 mmol, 1.0 equiv) in THF (500 mL) and CH2Cl2 (250 mL) at room temperature was added diisopropyl ethylamine (56.5 ml, 322.5 mmol, 3.0 equiv). The solution was cooled to 0° C. and allylchoroformate (11.5 ml, 107.9 mmol, 1.0 equiv) was added dropwise. The reaction was stirred at 0° C. for 1.5 hours, after which time saturated ammonium chloride (100 mL) was added and the THF and CH2Cl2 were removed under reduced pressure. The aqueous suspension was extracted with ether (4×300 mL). The organics were combined, washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (15→60% EtOAc/hexane) afforded 18 (30 g, 96%) as a white solid. Rf=0.43 (50% EtOAc/hexane); FTIR (neat, cm−1) 3297, 2959, 1734, 1688, 1566, 1518, 1441, 1229; 1H NMR (400 MHz, CDCl3) δ6.95 (d, J=7.9 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 5.85 (m, 1H), 5.24 (m, 3H), 4.6 (m, 1H), 4.53 (d, J=5.2, 2H), 3.71 (s, 3H), 3.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ172.3, 155.8, 155.2, 132.3, 130.3, 127.0, 118.0, 115.5, 66.0, 54.9, 52.9, 52.4, 37.4; HRMS (ES+) calculated for C14H17NO5 (M+H)+: 280.1107, found: 280.1195.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC)=O)=NC(OC)=O>O1CCCC1>[CH2:1]([C:35]1[CH:34]=[CH:33][CH:32]=[C:28]2[C:29]([NH:30][C:26](=[O:36])[C:27]=12)=[O:31])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCc1cccc2c1C(=O)NC2=O
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To solution (60 ml) of 5-(N-tert.butyloxycarbonyl, N-ethylamino)-1-pentanol (4.7 g) in anhydrous tetrahydrofuran were added triphenylphosphine (7.8 g) and phthalimide (4.4 g). To the solution was added dropwise dimethyl azodicarboxylate (5.2 g) with stirring under ice cooling. After stirring was made for one hour, the solvent was distilled off under reduced pressure. The residue was extracted with n-hexane-ethyl acetate (2:1). Solution extracted was washed with water and the solvent was distilled off to obtain N-[5-(N-tert.butyloxycarbonyl, N-ethylamino)] pentylphthalimide (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester (example 8 g]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{2-ethyl-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester as colorless liquid.