Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34](O)[CH2:33][CH2:32]1)(=[O:28])[CH3:27].OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[C:26]([O:29][CH2:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: CC(=O)OC[C@H]1CC[C@H](O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and (trans-4-hydroxycyclohexyl)methyl acetate (EXAMPLE 46, Step 1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:32])[C@@H:5]([CH3:31])[CH2:6][CH:7]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>>[C:27]([CH2:26][CH2:25][C:24]([NH:23][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)[CH2:6][C@H:5]([CH3:31])[C:4]([OH:32])=[O:3])=[O:30])([OH:29])=[O:28]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1-c1ccc(CC(C[C@H](C)C(=O)O)NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-4-(3-carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester was added 1M NaOH (2 ml) and stirred at room temperature for 2 hours. Then, to the mixture was added 2 ml of 1M HCl and concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (H2O (0.1% TFA)/CH3CN) to afford 110 mg of white powder. HPLC Retention time 0.86 minutes (condition A): MS 414.1 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 3 H) 1.28-1.48 (m, 1 H) 1.66-1.84 (m, 1 H) 2.24-2.39 (m, 5 H) 2.63-2.75°(m, 2 H) 3.75-4.02 (m, 4 H) 6.97-7.04 (m, 1 H) 7.09 (d, J=7.58 Hz, 1 H) 7.16-7.22 (m, 2 H) 7.24-7.29 (m, 1 H) 7.29-7.35 (m, 1 H) 7.35-7.41 (m, 2 H) 7.77 (d, J=8.59 Hz, 1 H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](OCC)=[O:7])C>Cl>[CH2:11]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCCCCCCCC(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Borane methyl sulfide (BMS) complex (80 g, 1 m) was added dropwise to a mixture of diethyl-n-octylmalonate (90 g, 0.33) and tolune (400 ml) with stirring at room temperature. Stirring was continued for an additional hour. The mixture was refluxed gently for 10 hours, cooled to 20° C., and then poured slowly into ice-cold methanol (400 ml) with stirring and left to stand overnight. The solvent was stripped off and the residue was stirred with 10% hydrochloric acid solution (400 ml) overnight. The resulting mixture was extracted with chloroform (2×70 ml) and washed with water until neutral to litmus. The solvent was evaporated and the residue was vacuum distilled to yield 2-n-octylpropane-1,3-diol (25.5 g, 41%) bp 135°-140° C./0.5-0.8 mm.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1nc(I)c2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2ccccc21
Yield: 69 %

Procedure:
A mixture of tert-butyl 3-iodo-1H-indazole-1-carboxylate (prepared as described in J. Med. Chem. (2008), 51(12), 3460-3465); (34 g; 99 mmol; 1.00 eq.), (trimethylsilyl)acetylene (16.6 mL; 119 mmol; 1.20 eq.), PdCl2(PPh3)2 (2.77 g; 3.95 mmol; 0.04 eq.) and TEA (41 mL) was heated overnight at 50° C. The reaction mixture was then diluted with DCM and washed three times with an aqueous saturated solution of NH4Cl. Organic layer was dried over magnesium sulfate, filtered and concentrated. This crude was solubilized in DCM and the precipitate obtained was removed by filtration through a celite pad. Purification by flash chromatography on silica (Heptane/EtOAc; gradient from 98:2 to 2:98) afforded the title compound as a beige solid (20 g, 69% yield). 1H NMR (300 MHz, DMSO-d6) δ: 8.12 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.70 (m, 1H), 7.46 (m, 1H), 1.65 (s, 9H), 0.32 (s, 9H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][C@@H:28]2[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]2)=[CH:24][CH:23]=1.[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:7](=[N:8][CH:9]([CH2:19][CH2:20][CH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][C@@H:28]2[CH2:32][O:31][C:30]([CH3:33])([CH3:34])[O:29]2)=[CH:24][CH:23]=1)[C:10]#[N:11])([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCBr)cc2)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(C#N)N=C(c3ccccc3)c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of N-(diphenylmethylene) aminoacetonitrile (5.14 g, 23.4 mmol) in DCM (12 ml) is treated with (R)-4-[4-(3-bromo-propyl)-phenoxymethyl]-2,2-dimethyl-[1,3]dioxolane (8.1 g, 24 mmol) in DCM (12 ml) and cooled to 0° C. 48% aqueous NaOH (20 ml) is added followed by benzyltriethylammonium chloride (530 mg, 2.4 mmol) and the resulting mixture is allowed to warm to room temperature. After stirring vigorously for 4 hours mixture is diluted with DCM (100 ml) and the aqueous portion is removed. The organic layer is washed with water (2×50 ml), brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by chromatography on silica eluting with 15:1 iso-hexane/diethyl ether to 4:1 iso-hexane/diethyl ether to yield 2-(Benzhydrylidene-amino)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]pentanenitrile as a yellow oil; 1H NMR (CDCl3): mix of diastereoisomers 1.39 (3H, s), 1.43 (3H, s), 1.71 (2H, m), 1.80-1.98 (2H, m), 2.52 (2H, tr, J=7.0 Hz) 3.90, (2H, m), 4.02 (1H, m), 4.10-4.22 (2H, m), 4.47 (1H, pent, J=6.9 Hz), 6.82 (2H, d, J=7.4 Hz), 7.05 (2H, d, J=7.4 Hz), 7.19 (2H, m), 7.35 (2H, tr, J=7.2 Hz), 7.40-7.50 (4H, m), 7.60 (2H, d, J=7.1 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[CH:19](=O)[CH3:20].ClCCl.[BH4-].[Na+]>O>[NH:1]([CH2:19][CH3:20])[C@H:2]([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: CC=O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NC
Yield: 89.8 %

Procedure:
A mixture of Tyr(3-tBu)-NHMe (1.7 g, 6.8 mmol), acetaldehyde (0.76 ml, 13.6 mmol) and dichloromethane (10 ml) was stirred under cooling with ice for 30 min. The reaction mixture was concentrated under reduced pressure under cooling with ice; the thus obtained residue was mixed with methanol (20 ml) and then under cooling with ice with sodium borohydride (0.28 g, 7.4 mmol) and stirred at the same temperature for 15 min. The resultant was mixed with water and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated under reduced pressure under cooling with ice; the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=20:1), giving N-Et-Tyr(3-tBu)-NHMe (T8) (1.7 g, 90%).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+].CO>O>[C:1](=[N:14][OH:15])([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1nccc2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1nccc2ccccc12
Reaction time: 16 h
Yield: 50.3 %

Procedure:
A solution of 1-acetyl-isoquinoline (3.42 g), hydroxylamine (1.53 g) and sodium acetate (2.46 g) in a 3:1 mixture of methanol:water (80 ml) was heated to reflux for 8 hours then allowed to stand for 16 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The combined extracts were dried, concentrated and chromatographed using ethyl acetate:hexane 3:7 as the eluant to give 1-acetyl-isoquinoline oxime (1.87 g, 58% yield) as a white crystalline solid m.p. 154.4°-155.3° C.; 1H NMR: 2.50(3H,s); 7.58-7.73(3H,m); 7.85(1H,m); 8.55(1H,m); 8.57(1H,m); 8.66(1H,s) ppm.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.C[O-:18].[Na+]>CO>[OH:18][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2c(cc1Cl)-c1ccccc1CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2c(cc1O)-c1ccccc1CC2

Procedure:
Add 23.1 gm of 2-chloro-5,6-dihydro-benzo[f]quinolin-3(4H)-one to 300 ml of methanol containing 30 gm of sodium methoxide. Heat the system in a steel bomb at about 200° C. for 12 hours. Stop the reaction, remove solvent, treat with water, and isolate the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:29])(=O)=O)=CC=1>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][Cl:29])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
2-(4-Acetylpiperazin-1-yl)ethanol (500 mg, 2.90 mmol), (prepared as described for the starting material in this example hereinbefore), was dissolved in methylene chloride (10 ml) and triethylamine (445 μl, 3.19 mmol) and 4-toluenesulphonyl chloride (609 mg, 3.19 mmol) were added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 1-acetyl-4-(2-chloroethyl)piperazine (300 mg, 54%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([OH:11])=[O:10])[CH2:3]1.[N+](=[CH2:14])=[N-]>O1CCCC1>[O:1]=[C:2]1[CH:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH3:14])=[O:10])[CH2:3]1
Reactant: O=C(O)C1=CCC2CC(=O)C12
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)C1=CCC2CC(=O)C12
Yield: 64 %

Procedure:
A solution of 800 mg of 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid in 10 mL of tetrahydrofuran was treated at room temperature with ethereal diazomethane. The crude reaction product was purified by chromatographic filtration through 10 g of silica gel (100-200 mesh), eluting with ether petroleum ether, first 2:3 and then 1:1, to afford 560 mg (64%) of methyl 7-oxobicyclo[3.2.0]hept-2-en-2-carboxylate as colorless crystals, mp 58° to 61°. IR (Nujol mull): 1630, 1715, 1790 cm-1 ; NMR (60 MHz, CDCl3): δ 2.5-3.3 (5H, m), 3.75 (3H, s), 4.3-4.6 (1H, m), and 6.90 (1H, broad s). HRMS: Calcd for C9H10O3, 166.0629; found, 166.0633.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.O>C(Cl)Cl>[N:1]1([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2o1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 0.75 h

Procedure:
Anhydrous piperazine (5.6 g) was dissolved in methylene chloride (100 ml) to which was subsequently added triethylamine (4.5 ml). With cooling in an ice bath, to this was added dropwise 2-chlorobenzoxazole (3.7 ml) in small portions, followed by 45 minutes of stirring. The reaction solution was mixed with water, extracted with methylene chloride and then washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic layer was dried with magnesium sulfate and the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (methanol) to obtain the title compound 2-(1-piperazinyl)benzoxazole,(4.751 g) in the form of yellow crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([O:19]CC)(=S)[C:15]([NH2:17])=O>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]2[C:3]=1[N:13]=[C:15]([NH2:17])[C:14](=[O:19])[NH:12]2
Reactant: CCOC(=S)C(N)=O
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1N
Solvent: CCCCO
Product: Nc1nc2c(Cl)cc(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 9.5 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 3-chloro-5-trifluoromethyl-1,2-phenylenediamine (420 mg, 2.00 mmol; Maybridge Co.) and ethyl thiooxamate (293 mg, 2.20 mmol; Aldrich Co.) in 4 mL of 1-butanol was heated to reflux. The resulting solution was stirred under reflux for 6 h. The resulting suspension was cool to 25° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 50 mg (9.5%) of 5-chloro-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid: mp 270°-272° C. 1H NMR (300 MHz, DMSO-d6) δ 12.043 (br s, 1H, NH), 7.561 (s, 1H, H-7), 7.463 (s, 1H, H-5). LRMS: 263 (M+, 100%), 235 (50%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccn(CCCO)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 51 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (99 mg, 74%) as a white foam: [α]30589=−27.3° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C20H25N3O2Cl2 (M+H)+ 410.1397, observed 410.1398; 1H NMR (400 MHz, DMSO-d6) δ 1.10 (m, 2H, CH2), 1.35-1.78 (m, 8H, 4×CH2), 1.85 (m, 2H, CH2), 2.04 (m, 1H, CH), 3.34 (t, J=6.4 Hz, 2H, OCH2), 3.79 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.56 (br, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.35 (dd, Jm=2.0 Hz, Jo=8.4 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.59 (d, Jo=8.4 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 10.71 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH3:11].S(=O)(=O)(O)O.[N+:17]([O-])([O-:19])=[O:18].[K+]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[C:5]([N+:17]([O-:19])=[O:18])=[C:4]([F:10])[C:3]=1[CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(F)cc(Cl)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c(Cl)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To 2,3,6-trifluoro-4-chlorotoluene (0.22 g) is added conc. sulfuric acid (3 ml) and the mixture is cooled to 0° C. Thereto potassium nitrate (0.18 g) is added and the mixture is stirred for 15 minutes under ice-cooling. The reaction mixture is poured into ice-water, extracted with dichloromethane, and the extract is washed with a saturated aqueous solution of sodium hydrogen carbonate, then with water and dried. The solvent is distilled off under reduced pressure to give 2,3,6-trifluoro-4-chloro-5-nitrotoluene (0.17 g).
Reaction SMILES: [CH2:1]([O:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:8][N:9]([C@H:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C@H:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:25][CH2:24]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of N-(benzyloxy)-2-nitrobenzenesulfonamide (212 g, 0.69 mol) in THF (1000 mL) was added (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (171 g, 0.63 mol) and PPh3 (275 g, 1.05 mol), followed by dropwise addition of a solution of DEAD (195 g, 1.12 mol) in THF (500 mL). The mixture was then stirred at 20° C. overnight. The reaction mixture was then concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (283.8 g, 80%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[NH:8])[NH2:7])[CH3:2].C(N(CC)CC)C.Br[CH:18]([CH3:22])[C:19](=O)[CH3:20]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:19]([CH3:20])=[C:18]([CH3:22])[NH:8][C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C(C)Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(N)[nH]c(C)c1C
Temperature: 5 °C
Yield: 35 %

Procedure:
To a solution of Carbamimidoyl-acetic acid ethyl ester (0.5 g) in ethyl acetate (6 mL) was added triethylamine (0.5 mL) and mixture was stirred at 5° C. Than 3-Bromo-butan-2-one (0.4 mL) was added under a nitrogen atmosphere and the mixture was refluxed for 1 h. The reaction mixture was then filtered through a medium porosity fitted glass funnel containing a thin layer of silica gel. The filtrate was washed with 100 mL of ethyl acetate and the combined washes were then evaporated under reduced pressure to give (0.25 g, 35%) of 2-Amino-4,5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [MH]+=183.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[C:1]([C:5]1[CH:10]=[C:9]([S:11][C:9]2([S:11][C:20]3[CH:21]=[C:22]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:17]([OH:23])=[C:18]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:19]=3)[CH2:10][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(C)(C)c1cc(SC2(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CCCCC2)cc(C(C)(C)C)c1O
Yield: 92.9 %

Procedure:
The procedure of Example 1 was repeated using 28.71 grams of 2.6-di-tert-butyl-4-mercaptophenol, 5.91 grams of cyclohexanone, and 150 ml of methyl alcohol. The product is triturated with methyl alcohol to give 31.17 grams (93.3% yield) of white solid, mp 195°-197° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][CH2:17][CH2:16][C@@:15]2([CH3:19])[C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:14]2[C@H:20]([CH3:30])[CH2:21]/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[C:26]([CH3:29])([OH:28])[CH3:27])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:28][C:26]([CH3:27])([CH3:29])/[CH:25]=[CH:24]/[CH:23]=[CH:22]/[CH2:21][C@H:20]([C@H:14]1[CH2:13][CH2:12][CH2:11][C@@H:10]2[C@:15]1([CH3:19])[CH2:16][CH2:17][CH2:18][C@@H:9]2[OH:8])[CH3:30]
Reactant: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@H](C/C=C/C=C/C(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Yield: 97.4 %

Procedure:
954 mg of (3E,5E)-(R)-8-[(1R,4aR,5S,8aR)-5-(tert-butyldimethylsilanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-2-methyl-nona-3,5-dien-2-ol were treated with 10 equivalents of anhydr. TBAF (2 M in THF) at 55° for 24 h. The reaction mixture was poured onto crushed ice/NH4Cl, extracted with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) yielded 685 mg of (1S,4aR,5R,8aR)-5-((3E,5E)-(R)-7-hydroxy-1,7-dimethyl-octa-3,5-dienyl)-4a-methyl-decahydro-naphthalen-1-ol as pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O[C:26](=[O:30])[CH2:27][C:28]#[N:29])C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:10]([CH3:11])=[C:27]([C:28]#[N:29])[C:26](=[O:30])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN=C(Sc2ccc(Cl)cc2)C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(Sc3ccc(Cl)cc3)c(C)c(C#N)c2=O)cc1
Temperature: 160 °C

Procedure:
A flasked equipped with a claisen distillation head and magnetic stirring was charged with an intimate mixture of 32.6 g (0.097 mole) 1-[(4-chlorophenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, 24.8 ml of ethylcyanoacetate and 12.2 g of ammonium acetate. The mixture was heated under a nitrogen atmosphere at 160° C. for 30 min. The reaction mixture was cooled and dissolved in methylene chloride. The organic layer was washed successively with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to yield semi pure product. The residue was recrystallized from 1900 ml of ethanol to yield 6-[(4-chlorophenyl)thio]-2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbontrile, mp 146-148° C. (EtOH).