Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22]=O)=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.CO.[CH3:32][NH2:33].[BH4-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[C:16]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][NH:33][CH3:32])=[CH:17][CH:18]=[CH:19][C:12]=3[N:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CN
Reactant: COc1cc(Cl)cc(C)c1Nc1nc2cccc(-c3ccccc3C=O)c2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CNCc1ccccc1-c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
A mixture of 33 mg (0.0813 mmol) of 2-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazol-7-yl]benzaldehyde, 0.033 mL (0.325 mmol) of 40% methanol solution of methyl amine and 1 mL of ethanol was refluxed for 4 hours. After cooling, 9.2 mg (0.244 mmol) of sodium borohydride was added. The mixture was stirred at room temperature for 4 hours, and 15 mg (0.407 mmol) of sodium borohydride was added. After stirring at room temperature for 15 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC and basic silica gel column chromatography eluting with a 50-100% ethylacetate/n-hexane gradient mixture to give 5 mg (17%) of the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1.C([O-])(=O)C([O-])=O>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:16][CH:15]=2)[CH2:29][CH2:30]1
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: COc1ccccc1N1CCN(CCCCNC(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 53 %

Procedure:
Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and 4-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butylamine according to the general procedure. Yield: 53%. Mp. (oxalate): foam. 1H NMR (CDCl3): δ1.67-1.74 (m, 4H), 2.49 (t, J 6.84, 2H), 2.67 (s, 2H), 3.07 (s, 2H), 3.51 (q, J 6.0, 2H), 3.84 (s, 3H), 6.83 (m, 5H), 7.26 (m, 1H), 7.73-7.79 (m, 2H), 7.89 (d, J 8.2, 2H), 8.06 (d, J 8.6, 2H), 8.71 (dt, J 4.7, 1.3, 1H). 13C NMR (CDCl3): δ 24.8, 27.9, 40.4, 50.8, 53.9, 55.8, 58.5, 111.6, 118.7, 121.3, 121.4, 128.1, 123.4, 127.4, 127.9, 135.6, 137.3, 142.5, 150.3, 152.7, 156.7, 167.8. Anal. (C27H32N4O2.(COOH)2.0.75H2O) C, H, N.|
Reaction SMILES: [CH2:1]([N:4]([C:10]([O:12][CH3:13])=[O:11])[CH2:5][C:6](OC)=O)[C:2]#[CH:3].[NH3:14].C[OH:16]>>[CH2:1]([N:4]([C:10]([O:12][CH3:13])=[O:11])[C:5](=[O:16])[CH2:6][NH2:14])[C:2]#[CH:3]
Reactant: CO
Reactant: N
Reactant: C#CCN(CC(=O)OC)C(=O)OC
Product: C#CCN(C(=O)CN)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.9 g of methyl N-propargyl-N-methoxycarbonylglycinate were added to the mixture of 100 ml of 28% aqueous ammonia and 10 ml of methanol and stirred for 10 hours at room temperature. Then the solvent was evaporated off from the reaction mixture. The residue was chromatograhed on silica gel to obtain 3.0 g of N-propargyl-N-methoxycarbonylglycinamide (melting point: 77°-80° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:11][NH2:12])=[N:6][CH:7]=1
Reactant: NN
Reactant: Fc1cc(Br)cnc1F
Solvent: O
Solvent: CCO
Product: NNc1ncc(Br)cc1F
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 5-bromo-2,3-difluoropyridine (15 g, 77 mmol)) in EtOH (250 ml) was added hydrazine hydrate (19.36 g, 387 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (15 g, yield 94%). LCMS (method A): [M+H]+=206.0, 208.0, tR=1.01 min.
Reaction SMILES: C[C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[H][H].[CH2:15](O)C>[Pd]>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][C:7]([CH3:15])=[CH:2][C:3]=1[NH2:10]
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Product: COc1ccc(C)cc1N

Procedure:
Palladium charcoal (1.0 g of 10%) was added to a solution of 3-methyl-2-nitroanisole (16.8 g, 0.1 mol) in ethanol (150 mL) and the solution was hydrogenated (50 lb initial hydrogen pressure) until hydrogen uptake ceased (2 hours). The solution was filtered and evaporated to give 13.8 g of 2-methoxy-5-methylbenzenamine (compound XLIV) as an oil. The product was dissolved in acetic anhydride (100 mL) and the resulting solution was refluxed for 1 hour. Part of the solvent (50 mL) was slowly removed over a 1-hour period, after which time the solution was cooled and the remainder of the solvent was removed under reduced pressure. The residual oil was crystallized from ethyl acetate:hexane (200 mL of 1:2) to give 20.5 g of N-acetyl-N-(2-methoxy-6-methylphenyl)-acetamide, mp 115°-119° C. Anal Calcd for C12H15NO3 : C, 65.14; H, 6.83; N, 6.33. Found: C, 65.44; H, 7.04; N, 6.39.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]([OH:29])=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=3)=[C:14]([F:30])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31](OCC)(=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]3[C:21]4[O:29][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][C:26](=[O:28])[C:22]=4[CH:23]=[CH:24][CH:25]=3)=[C:14]([F:30])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2F)c1O
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3F)c2o1

Procedure:
Following the process described in example 1 (point A), starting from 3'-[(E)-2-[4-(4-phenylbutoxy)-2-fluorophenyl]ethen-1-yl]-2'-hydroxy-acetophenone and diethyl oxalate, the title compound was prepared (quantitative yield).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH:12]=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH2:21][CH2:22][CH2:23][NH2:24].CO.[BH4-].[Na+]>ClCCl>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH2:21][CH2:22][CH2:23][NH:24][CH2:12][C:10]1[S:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][N:9]=1
Reactant: CC1CCCCN1CCCN
Reactant: O=Cc1ncc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1CCCCN1CCCNCc1ncc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Experimental condition analogous to Example 18, from 5-phenyl-thiazole-2-carbaldehyde 0.16 g (1.05 mmol), 3-(2-methyl-piperidin-1-yl)-propylamine 0.2 g (1.05 mmol), in 5 mL of dry dichloromethane was added 2 g of molecular sieve. The reaction was stirred overnight at room temperature. The molecular sieve was filtered and dichloromethane was concentrated under vaccum. To the mixture was added 15 mL of dry methanol and sodium borohydride 0.04 g (1.155 mmol) was added at 0° C. after 30 minutes reaction goes to completion. The reaction was quenched with 2 mL acetone, methanol was concentrated under vacuum, and was diluted with chloroform, organic layer was washed with 2 times 20 mL water, followed with brine. The organic layer was dried over magnesium sulfate and concentrated under vaccum. Yield 0.3 g of compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1>ClCCl.O>[CH3:8][S:9]([O:13][CH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CO)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COS(C)(=O)=O)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
Triethylamine (990 μL, 7.1 mmol, 1.2 equiv) and methanesulfonyl chloride (500 μL, 6.5 mmol, 1.1 equiv) were sequentially added to a stirred solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (840 mg, 5.7 mmol, 1.0 equiv) in dichloromethane (15 mL) at 23° C. The resulting bright yellow solution was stirred at 23° C. for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (1.1 g, 85%): 1H NMR (300 MHz, CDCl3) δ 4.33 (s, 2H), 4.16 (q, J=7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J=7, 4 Hz, 2H), 1.26 (t, J=7 Hz, 3H), 1.04 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1ccc(COc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 4-methylbenzyl chloride (4.78 ml), potassium carbonate (6.24 g), methyl iodide (5.41 g) and acetone (50 ml) was heated at reflux for 15 hours. After the reaction mixture was evaporated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(4-methylbenzyloxy)benzoic acid (5.92 g) as colorless crystals.
Reaction SMILES: N1C2C=CC=[C:9]([CH:10]=[O:11])C=2N=N1.N[C:13]1[CH:21]=[CH:20][C:16]2[NH:17][N:18]=[N:19][C:15]=2[CH:14]=1.C(=NO)C>C(Cl)Cl>[C:10]([C:13]1[CH:21]=[CH:20][C:16]2[NH:17][N:18]=[N:19][C:15]=2[CH:14]=1)(=[O:11])[CH3:9]
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: O=Cc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CC=NO
Product: CC(=O)c1ccc2[nH]nnc2c1

Procedure:
The ketone was prepared in the same manner as the benzotriazole aldehyde from 5-aminobenzotriazole and acetaldoxime. Column chromatography of the crude ketone using DCM and eluting with MeOH (0-10%) afforded the ketone in 11% yield. Rf [A] 0.3; δH(400 MHz; Acetone-d6) 2.68 (3H, s, CH3), 7.92 (1H, d, J 8.7, Ar—H), 8.07 (1H, d, 3 8.7 Ar—H), 8.62 (1H, s, Ar—H); m/z (FAB−HR) 162.06674 [(M+H)+ calc. for C8H8N3O 162.06682]. The hydrazone of the ketone was prepared from 2,4DNPH to afford an orange solid. 4,6-Dinitro-7-1H-benzotriazole [26]
Reaction SMILES: [CH3:1][CH:2]([S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:18][CH:17]=1)[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: CC(C)CCCC(C)Sc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(SC(C)CCCC(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)thio]benzoic acid and propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)thio]benzoic acid propargyl ester M.P. 130°-131° C./0.03 mmHg.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:26](I)=[C:25]([CH3:28])[O:24][N:23]=1>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)=[C:25]([CH3:28])[O:24][N:23]=1
Reactant: Cc1onc(-c2ccc(F)cc2F)c1I
Reactant: CC(C)c1nnc2ccc(I)nn12
Product: Cc1onc(-c2ccc(F)cc2F)c1-c1ccc2nnc(C(C)C)n2n1
Yield: 22.1 %

Procedure:
6-Iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.400 g, 1.25 mmol, Preparation #H.1) and 3-(2,4-difluorophenyl)-4-iodo-5-methylisoxazole (0.360 g, 1.25 mmol) were coupled using General Procedure I.1 to provide the title compound (0.098 g, 22%): LC/MS (Table 1, Method g) Rt=2.16 min; MS m/z: 356.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][OH:19])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]=[O:19])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)Nc1cc(Cl)ccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(Cl)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
To a solution of N-(benzylcarbonyl)-5-chloro-2-hydroxymethyl aniline (15.50 g) in dichloromethane (400 ml) under nitrogen at room temperature, was added pyridinium chlorochromate (24.30 g) and crushed 4 Å molecular sieves (0.50 g). The reaction mixture was stirred at room temperature for 90 mins, then ethyl acetate added, and the solution was filtered through a 2 inch plug of silica gel. The solvent was removed in vacuo and the material was redissolved in ethyl acetate and filtered through silica gel. Removal of the solvent under vacuum and trituration of the solid residue with diethyl ether gave the desired compound (10.50 g). δ (360 MHz, DMSO-d6) 3.82 (2H, s, NHCOCH2Ph), 7.27-7.39 (6H, m, Ph+5-H), 7.87 (1H, d, J=8.30 Hz, 6-H), 8.36 (1H, d, J=1.87 Hz, 3-H), 9.89 (1H, s, CHO), 10.97 (1H, bs, NHCOCH2Ph).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:21][C@@H:22]([CH2:52]O)[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:64]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:29][C:26]1[CH:27]=[CH:28][N:24]([CH2:23][C:22]([OH:21])([CH3:52])[CH3:64])[N:25]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCO1)C(=O)O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Yield: 57.1 %

Procedure:
To a solution of (S)-2-t-butoxycarbonylamino-3-(tetrahydro-pyran-2-yl)-propionic acid (700 mg, 2.56 mmol) in N,N-dimethylformamide (6 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 398 mg, 2.57 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.36 g, 3.0 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.4 mL) was added. The mixture was stirred at room temperature overnight and solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. Solvents were evaporated and the residue was purified through flash column chromatography (silica gel, 5 to 100% ethyl acetate/hexanes) to afford [(S)-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-2-yl)-ethyl]-carbamic acid t-butyl ester (600 mg, 57%) as a white solid: LR-ES-MS m/z calculated for C20H34N4O5 [M]+ 410, observed [M+H]+ 411.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.Cl>[Fe].C(O)C>[N:8]1([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:16]=[CH:15][CH:14]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(CN2CCOCC2)c1

Procedure:
A 250-mL, three-neck, round bottomed flask equipped with a mechanical stirrer and reflux condensor was charged with compound 9 (12.7 g, 57.4 mmol), iron powder (40.0 g, 71.7 mmol), 2N hydrochloric acid (20 mL) and ethanol (75 mL). The resulting suspension was heated at reflux for 2 h. After this time the mixture was allowed to cool and filtered through a pad of CELITE® 521. The filtrate was concentrated under reduced pressure, the residue diluted with water (100 mL) and basified with solid potassium carbonate to pH 10. The mixture was extracted with ethyl acetate (3×75 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield compound 8 as a dark viscous oil. 1H NMR (CDCl3) δ(ppm) 7.09 (t, 1H, J=8.1 Hz), 6.70 (m, 2H), 6.58 (m, 1H), 3.70 (m, 4H), 3.40 (bs, 2H), 2.44 (m, 4H). Intermediate compound 8 is shown below.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[C:11]([CH:24]=[O:25])[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M in hexane) (0.83 mL, 2.2 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (54 mg, 2.2 mmol) in tetrahydrofuran (5 mL). After stirring at −78° C. for 10 min, N,N-dimethylformamide (0.17 mL, 2.2 mmol) was added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for a further 5 min, the reaction mixture was quenched with water and extracted with methylene chloride. The combined aqueous phases were dried (magnesium sulfate) and concentrated. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][SH:31])=[CH:25][CH:24]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6]([S:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: Fc1ccc(CCS)cc1
Reactant: O=C(O)Cc1ccc(CC(Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(O)Cc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-phenyl)-2-chloro-propionic acid 2,2,2-trichloro-ethyl ester (1.17 g, 3.13 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (0.53 g, 3.44 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After purification by flash chromatography with n-heptane/EtOAc 10:1 as the eluent the product was obtained as a solid (611 mg, 39.6%). 1H NMR (300 MHz, CDCl3): δ 7.09-7.23 (m, 6H), 6.94-6.99 (m, 2H), 4.65-4.77 (q, 2H), 3.56-3.61 (m, 3H), 3.18-3.28 (dd, 1H), 2.78-3.02 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.323 g. of caproic acid chloride as in Example 1. The 0.613 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.555 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl hexanoate obtained melts at 56.1° and has a clearing point of 70.7° UV (EtOH): ε 273 = 26400.
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH3:15]>ClCCl>[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([O:24][CH2:1][O:2][CH3:3])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CN1CCc1ccc(OC)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](OCOC)CN1CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
9.32 ml (123 mmol) of MOMCl was added to a solution of 25 ml (144 mmol) of N,N-diisopropylethylamine and 6.00 g (20.5mmol) of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidine in dichloromethane (100 ml) and the mixture was stirred for 14 hours at room temperature. The mixture was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:1) to give 6.20 g of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidine in 89.8% yield.