Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]S([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][CH2:9][C@H:10]([NH:22]C(=O)OC(C)(C)C)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.O>C(#N)C>[ClH:1].[C:6](=[O:7])([O:8][CH2:9][C@H:10]([NH2:22])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1)[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Product: Cl
Product: NC(=O)OC[C@H](N)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
At −15° C., 38 μl (0.44 mmol) of chlorosulphonyl isocyanate were added slowly to a solution of 100 mg (0.31 mmol) of (2R)-tert-butyl {1-hydroxy-3-[3-(trifluoromethyl)phenyl]propan-2-yl}carbamate (for the preparation see US patent application 2008/0242694, Example [0440]) in 2 ml of acetonitrile. The reaction mixture was stirred at RT for 1 h, 3 ml of water were then added and the mixture was heated under reflux overnight. After cooling to RT, the mixture was purified directly by preparative HPLC [Method 9]. This gave a first fraction (21 mg) of the title compound (in part as formate salt) and a fraction (17 mg) of the corresponding compound which was still Boc-protected. The latter fraction was stirred for 30 min with 3 ml of a 4 N solution of hydrogen chloride in dioxane and then freed from the volatile components on a rotary evaporator and then under high vacuum. The residue (16 mg) corresponded to the pure title compound. Both fractions of the title compound were combined and used to prepare subsequent compounds.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Cl[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=1.Cl>CS(C)=O>[OH:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][C:14]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1cc(CNS(C)(=O)=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 1.60 g, 40.0 mmol) in 25 mL DMSO under Argon was added dropwise a solution of methanesulfonamide (3.80 g, 40.0 mmol) in 10 mL DMSO. The resulting mixture was stirred 30 minutes and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (3.69 g, 20.0 mmol) in 10 mL DMSO was added. The resulting mixture was stirred three hours, poured into 150 mL ice water, acidified with 14 mL 3N hydrochloric acid, and the mixture extracted with methylene chloride (3×200 mL). The extract was washed with water (50 mL) and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give an oil which was partially purified by flash chromatography eluting with 3:97 methanol:chloroform to give a gum. The gum was stirred under 25 mL water to remove residual DMSO, the aqueous supernatant.was decanted, and the residue was dried in vacuo. The resulting material was crystallized from ethylacetate to remove 0.67 g of a by-product identified as N,N-bis[(3-acetyl-4-hydroxyphenyl)methyl]methanesulfonamide. The mother liquor was concentrated in vacuo to give a residue which was re-chromatography to give a solid. The solid was recrystallized from n-butylchloride to give 0.60 g (12%) product, as a white solid, mp 85°-86.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:9]([N:8]=[C:3]1[NH:4][C:5](=[O:7])[CH2:6][N:2]1[CH3:1])=[O:11]
Reactant: Nc1ccccn1
Reactant: CN1CC(=O)NC1=NC(=O)O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccccn1
Temperature: 90 °C

Procedure:
A mixture of 2.7 g (11.6 mM) of the phenyl ester of tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene carbamic acid 8 and 10.0 g (106 mM) of 2-aminopyridine was heated at 90° C. for 1 hr. The excess amine was removed by vacuum distillation and the residue triturated with 35 ml. ethanol, filtered and the collected solid recrystallized from ethyl acetate to give 1.1 g of the above urea as a cream colored solid, m.p. 218° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12]2[C:21]3[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=3[C:19]3[C:14](=[CH:15][CH:16]=[N:17][CH:18]=3)[N:13]=2)=[C:6]([Cl:27])[CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Br>C1COCC1>[Cl:27][C:6]1[CH:5]=[C:4]([C:1]([OH:3])([CH3:28])[CH3:2])[CH:9]=[C:8]([Cl:10])[C:7]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(4-acetyl-2,6-dichlorophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Examples 144 and 145, Step 3) (1.3 g, 3.26 mmol) in THF (30 mL) at 0° C. under nitrogen atmosphere was added methyl magnesium bromide (11.6 mL, 1.4 M in THF/toluene) and the reaction mixture stirred for 30 min. The solution was quenched with 1 N citric acid, diluted with 1:1 THF/EtOAc, and neutralized with saturated NaHCO3. The organic layer was concentrated, triturated with diethyl ether, and filtered to afford the desired product as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:30])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:31]#[N:32])=[CH:13][CH:12]=2)=[O:10])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)C(F)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C(F)C(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Yield: 103.7 %

Procedure:
A flask was charged with tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetate (0.026 g), 0.5 ml of dichloromethane and 0.2 ml of TFA. The reaction was concentrated, and the residue was dissolved in a minimal amount of dichloromethane and placed under high vacuum to give a solid. The procedure was repeated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetic acid (0.024 g) as a tan solid.
Reaction SMILES: [CH2:1]([C:4]1([C:25](O)=[O:26])[N:8]2[C:9](=[O:24])[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[CH:11][N:12]=[C:7]2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:28]([O:32][C:33](=[O:45])[NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29]>>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:10]1[C:9](=[O:24])[N:8]2[C:4]([CH2:1][CH:2]=[CH2:3])([C:25](=[O:26])[NH:44][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:45])=[NH:36])=[CH:42][CH:41]=3)[CH2:5][CH2:6][C:7]2=[N:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Reactant: C=CCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Product: C=CCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 86 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 20b (50 mg, 0.135 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 70 mg (86%) of intermediate 20c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CON
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(OC)cc1
Yield: 100 %

Procedure:
Reaction of 4-methoxybenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.89 (2H, m, aromatics), 7.52 (2H, m, aromatics), 8.05 (1H, s, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]([CH3:34])[NH:29][CH2:28][CH2:27]3)=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)[CH:25]=4)[CH:30]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ncc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.[CH2:36](N(CC)CC)C>CN(C)C=O.O>[CH3:36][C:14]1([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][C:23]([F:35])([F:34])[F:22])=[CH:26][CH:27]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(N2Cc3cc(CNC(=O)c4ccc(OC(F)(F)F)cc4)ccc3C2=O)CCC(=O)NC1=O
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.4 g, 1.20 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.27 g, 1.20 mmol) in N,N-dimethylformamide (15 mL), was added triethylamine (0.34 mL, 2.40 mmol) at room temperature under nitrogen. After 2 h, the mixture was diluted with water (60 mL) and stirred for 1 h. The product was isolated by filtration, washed with water (50 mL) and dried in vacuo providing N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (0.41 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.81 min (95.39%); mp: 224-226° C.; 1H NMR (DMSO-d6) δ 1.66 (s, 3H), 1.82-1.94 (m, 1H), 2.52-2.82 (m, 3H), 4.48-4.69 (m, 4H), 7.38-7.56 (m, 4H), 7.61 (d, J=7.9 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 9.28 (t, J=5.5 Hz, 1H), 10.86 (s, 1H); 13C NMR (DMSO-d6) δ 20.74, 27.81, 29.01, 42.78, 47.64, 57.12, 119.9 (q, J=256 Hz), 120.68, 121.82, 122.58, 127.04, 129.60, 131.02, 133.36, 142.41, 143.57, 150.34, 165.06, 167.00, 172.44, 173.55; LCMS: MH=476; Anal Calcd for C23H20F3N3O5+0.7H2O: C, 56.61; H, 4.42; N, 8.61. Found: C, 56.60; H, 4.11; N, 8.61.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:11]#[C:12][Si](C)(C)C)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C:5]1[C:6]([C:11]#[CH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ncccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.5 g, 41 mmol) in THF (200 mL) was added water (25 ml). The reaction was cooled to 0° C. and TBAF (1M, 45 ml, 45 mmol) was added. The mixture warmed to ambient temperature and stirred for 1 hour. Water (100 mL) was added and the volume was reduced by half. The product was extracted into ether (3×100 mL), washed with brine and dried over MgSO4. The solution was concentrated in vacuo to afford 2-ethynylpyridin-3-yl acetate (5.5 g, 34 mmol) as a light brown oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:3][CH2:2]1.[C:19]1([C:25]2[O:26][C:27]([C:33]([F:36])([F:35])[F:34])=[C:28]([C:30](O)=[O:31])[N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:18])[C:9]2[N:10]=[CH:11][C:12]([NH:15][C:30]([C:28]3[N:29]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:26][C:27]=3[C:33]([F:35])([F:36])[F:34])=[O:31])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(CCOCC1CC1)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCOCC1CC1)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 63.3 %

Procedure:
(2-Cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (82 mg, 0.326 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (92 mg, 0.359 mmol), Et3N (229 uL, 1.63 mmol) and BOP (151 mg. 0.326 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a solid (95 mg). ES-MS calcd for C23H23F3N4O3 (m/e) 460.46, obsd 461.1 (M+H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C-]#N.[Na+].[CH:17](=[CH:24][C:25](=[O:27])[CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:24][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccccc1
Yield: 66.6 %

Procedure:
A solution of 21.2 g (0.2 mol) of benzaldehyde and 100 ml of absolute dimethylformamide is added dropwise in the course of 1/2 hour to a mixture of 4.9 g (0.1 mol) of NaCN and 100 ml of absolute dimethylformamide in a manner analgous to Example 3. Stirring is then continued for 11/2 hours at 35° C. A solution of 21.9 g (0.15 mol) of benzalacetone and 100 ml of dimethylformamide is then slowly added dropwise in the course of 31/2 hours at 35° C. Stirring is then continued for 31/2 hours at the same temperature. The reaction mixture is treated with twice its quantity of water and the product is worked up in a manner analogous to Example 5. 43.5 g of crude product are obtained from which 25.2 g of 1,4-dioxo-1,2-diphenyl-pentane (67% of theoretical) are obtained by distillation. B.p.: 166° C/0.4 mm Hg; m.p.: 60°-61° C C17H16O2 (253.3) Calculated: C, 80.92; H, 6.39. Found: C, 80.62; H, 6.50.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:14]([Li])([CH2:16][CH3:17])[CH3:15].[CH2:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH2:6]([O:5][P:4]([CH:9]([CH2:15][CH2:14][CH2:16][CH2:17][CH2:23][CH2:24][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=CCCCP(=O)(OCC)OCC
Reactant: [Li]C(C)CC
Reactant: C1CCCCC1
Solvent: C1CCOC1
Product: C=CCCC(CCCCCCCCCC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of 4-pentenyl phosphonic acid diethyl ester (2.832 g, 13.7 mmol) in anhydrous tetrahydrofuran (20 mL) and cooled to about −78° C. A 1.3 M solution of sec-butyl lithium in cyclohexane (15 mL, 19.5 mmol) was added slowly to the mixture keeping the temperature below −60° C. 1-lododecane (6.32 g, 23.6 mmol, 1.8 eq.) was then added slowly to the reaction mixture. The mixture was warmed to 0° C. and was stirred for three hours. The reaction was then quenched with NH4Cl (saturated, 20 mL). The mixture was warmed to room temperature and the THF was removed by rotary evaporation. The resulting solution was extracted with ethyl acetate (50 mL). The organic layer was separated and dried over Na2CO3. The solvent was removed and the resulting residue was purified by column chromatography (silica, ethyl acetate/hexane=2/8 then 4/6) to provide the pure product (3.46 g, 73% yield). 1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 4.1 (m, 4H), 2.2 (m, 2H), 1.8–1.2 (m, 27H), 0.9 (t, 3H). 31P NMR (CDCl3) δ=35.8.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6](=O)[CH2:5]1)(=O)[NH2:2]>C1COCC1>[NH2:2][CH2:1][CH:4]1[CH2:5][CH2:6][N:7]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:8]1
Reactant: NC(=O)C1CC(=O)N(Cc2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 1.0 M THF solution of BH3 (25 mL) was added to a THF (15 mL) solution of 4-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g). The resulting reaction mixture was stirred for 15 hours and cooled to room temperature. The solvent was then removed under reduced pressure. Water (30 mL) and concentrated hydrochloric acid (10 mL) were added, and the mixture was stirred at 100° C. for 2 hours and at room temperature for 1 hour. A 2 M aqueous solution of NaOH (100 mL) was added, and the obtained mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over K2CO3, filtered, concentrated and purified by column chromatography (SiO2, 15% methanol-5% triethylamine/dichloromethane) to thereby afford 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 19%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][OH:16].Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Reactant: COC(=O)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
Sodium hydride (60%, oily, 1.80 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (8.51 g) in tetrahydrofuran (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. A solution of methyl 6-chloro-2-pyridinecarboxylate (7.72 g) in tetrahydrofuran (75 ml) was added to the mixture. After being stirred at 40° C. for 5 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain methyl 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridinecarboxylate (7.41 g, yield 51%) as yellow crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].CO.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[OH-].[Na+]>C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.CCOCC.CO>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of α-bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p-chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100° bath and stirred at 100° for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous phase is acidified to pH 4 and extracted with ether. The ether extracts are combined and washed with brine, dried over sodium sulfate and stripped to yield N-(p-chlorophenyl)valine.
Reaction SMILES: [H-].[Na+].C([CH:5]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)#N.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:27](=[O:28])[CH:5]([O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:25][CH:24]=1
Reactant: N#CC(OC(=O)c1ccccc1)c1cccnc1
Reactant: COc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)C(OC(=O)c2ccccc2)c2cccnc2)cc1
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of sodium hydride (0.27 g, 6.72 mmol) in 10 mL of tetrahydrofuran was slowly added benzoic acid cyano-pyridin-3-yl-methyl ester (1.24 g, 5.61 mmol) prepared in Step 1 at 0° C. After addition was complete, the reaction solution was elevated to room temperature and stirred for 3 hours. Thereafter, 4-methoxybenzaldehyde (0.84 mL, 6.72 mmol) was additionally added to the resulting solution which was then stirred for 3 hours. After the reaction was complete, the reaction materials was diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 1.21 g (yield: 60%) of benzoic acid 2-(4-methoxy-phenyl)-2-oxo-1-pyridin-3-yl-ethyl ester of the following formula.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][OH:12])[N:6]=1)=[O:4].[OH:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[C:18](O)[CH:17]=[CH:16][C:15]=1[C:24](=[O:26])[CH3:25].C(P(CCCC)CCCC)CCC.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>C1COCC1.C(OCC)(=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:18]2[CH:17]=[CH:16][C:15]([C:24](=[O:26])[CH3:25])=[C:14]([OH:13])[C:19]=2[CH2:20][CH2:21][CH3:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(CO)n1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2cccc(C(=O)OC)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 83.2 %

Procedure:
Combine 6-hydroxymethyl-pyridine-2-carboxylic acid methyl ester (2.20 g, 13.2 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2.56 g, 13.2 mmol), and tri-n-butylphosphine (3.94 mL, 15.8 mmol) in THF (45 mL). Add diethyl diazodicarboxylate (3.98 g, 15.8 mmol). After 12 hours at ambient temperature, add diethyl ether (white precipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography eluting with 3:7 hexane:ethyl acetate to obtain the title compound as a white solid (3.769 g, 10.98 mmol): mass spectrum (m/e): 344 (M+1).