Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[CH3:11][NH:12][CH:13](SC)[CH2:14][N+:15]([O-:17])=[O:16]>CCO>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:13]([NH:12][CH3:11])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CNC(C[N+](=O)[O-])SC
Reactant: NCc1ccc(Cl)nc1Cl
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1Cl
Yield: 27.3 %

Procedure:
A mixture of 1.2 g (0.007 mole) of (2,6-dichloro-3-pyridylmethyl)amine and 1 g (0.007 mole) of 1-methylamino-1-methylthio-2-nitroethane was refluxed in 50 ml of EtOH for 6 hours. After cooling, the reaction mixture was concentrated and the resulting crystals were collected by filtration, washed with CH2Cl2 and a small amount of EtOH in that order and dried. The procedure gave 0.53 g of the title compound as a white powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[CH:11](=O)/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.C(OCC)(=O)CC(C)=O>[CH2:8]([O:7][C:1]([CH:2]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH:11]=[CH:5][C:3]1=[O:4])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C/C=C/c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)C=CCC1c1ccccc1
Yield: 100 %

Procedure:
The reaction was repeated replacing the sodium metal with ethyl acetoacetate, sodium salt. Thus, 12.6 grams (0.097 mole) of ethyl acetoacetate, 0.5 gram (0.003 mole) of ethyl acetoacetate, sodium salt and 13.2 grams (0.100 mole) of trans-cinnamaldehyde in 50 mL of ethanol were reacted in a manner analogous to that of Example 6, Step A. A 100% yield (24.4 grams) of 2-ethoxycarbonyl-3-phenylcyclohex-5-enone was assumed.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:22][C@H:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[O:25])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:26][C:24](=[O:25])[C@H:23]([NH:22][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:27][CH3:28]
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3ccncc3)cc2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3ccncc3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(4-(pyridin-4-yl)phenylamino)pyrazin-2-ylamino)butanamide (57 mg, 0.152 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 392.3 (M+H); UV 204.2, 244.4, 281.2, 360.0 nm; t 0.404 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][Si:18](Br)([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: C[Si](C)(C)Br
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Yield: 75.1 %

Procedure:
A solution of 60 ml of benzene, 5.0 g (30.9 mmole) of 2,6-dichloroaniline, 10.6 ml (76.0 mmole) of triethylamine, and 8.08 ml (61.1 mmole) of trimethylsilyl bromide was heated at reflux for 54 hours, cooled, filtered, and the solvent was removed from the filtrate in vacuo. The residue was evacuated at 1 mm to remove any excess trimethylsilyl bromide. The residual mixture was filtered into a round-bottomed flask and distilled using a short Vigreaux column to provide 5.43 g (23.2 mmole, 75.0 percent yield) of the N-trimethylsilyl-2,6-dichloroaniline as a 97 percent pure amber oil, bp 74° C.-75° C. at 0.4 mm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]([CH3:9])=[CH:6][C:4]([NH2:5])=[C:3]([CH3:10])[C:2]=1[Cl:1]
Reactant: Cc1cc(N)c(C)c(Cl)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(N)c(C)c(Cl)c1Br
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To a solution of compound 21B (1.56 g, 10 mmol) in CHCl3 (30 mL) cooled to 0-5° C. was added portionwise tetrabutylammonium tribromide (434 mg, 9.0 mmol). After addition, the reaction was stirred at 0-5° C. for 5 min, then quenched with saturated aqueous NaHCO3 (30 mL) and 5% aqueous Na2S2O3 (30 mL). The mixture was stirred at rt for 10 min, then extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 20-60% EtOAc/hexane to give the title compound (0.75 g, 32% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C>[OH:19][CH2:18][CH2:17][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCCCl
Reactant: Oc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCSc1ccc(O)cc1
Reaction time: 8 h

Procedure:
4-Hydroxythiophenol (6.31 g, 50 mmol) was dissolved in ethanol (100 mL) and potassium tert-butoxide (6.72 g, 60 mmol) was added. The mixture was stirred until a clear, yellow solution was obtained. Then 3-chloro-1-propanol (4.20 ml, 50 mmol) was added with a syringe. The reaction mixture was stirred overnight at room temperature, the potassium chloride precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and the organic layer was extracted with water (2×100 mL) and brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (50 mL) and hexane (100 mL) and left standing open overnight. The solid product was filtered off and dried under high vacuum. Yield: 5.34 g (58%) pale yellow solid.
Reaction SMILES: [CH:1]([CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=[O:2].[H-].[Na+].[CH3:19]I>O1CCCC1>[CH:1]([C:3]1([CH3:19])[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: CI
Reactant: Cn1c2c(c3ccccc31)SCCC2C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3ccccc31)SCCC2(C)C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
A solution of 4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (2.31 g) in dry tetrahydrofuran (25 ml) is mixed with 50% sodium hydride (480 mg) and stirred at room temperature for 1.5 hours. Under ice cooling, a solution of methyl iodide (1.7 g) in dry tetrahydrofuran (5 ml) is added dropwise thereto over 5 minutes. The mixture is stirred further for 1.5 hours at room temperature and poured into ice water, which is extracted with ether. The extract is washed with water, dried and evaporated to dryness. The residue is applied to liquid chromatography eluted with benzene/hexane (5:1) to give the title compound (1.62 g): Yield 66.2%.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH2:12][N:11]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[N:11]1[CH2:12][CH2:13][CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])CC1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2N)CC1O[Si](C)(C)C(C)(C)C
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-4-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-ylcarbamate, (>99%). LCMS (m/z): 423.3 (MH+); LC Rt=3.62 min.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Sn](C)(C)C)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].Br[C:22]1[C:23]2[C:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=3[CH:35]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.N#N>CN(C=O)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C(Cl)Cl>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:22]2[C:23]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[CH:35]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: COC(=O)[C@H](Cc1ccc([Sn](C)(C)C)cc1)NC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(-c2cc3ccccc3c3ccccc23)cc1)NC(C)=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
A solution of 95 (259 mg, 0.67 mmol), 9-bromophenanthrene (190 mg, 0.74 mmol), palladium acetate (8 mg, 0.034 mmol), and tri-o-tolylphosphine (20 mg, 0.067 mmol) in DMF (2 mL) was flushed with N2 for 15 min then heated to 70° C. and allowed to stir for 16 h. The reaction was diluted with diethyl ether (20 mL) and washed with water (5×20 mL), dried and evaporated. The crude product was purified by flash column chromatography (15% EtOAc/hexane then 5% MeOH/DCM) to yield the title compound (157 mg, 0.40 mmol, 59%) as a clear oil. [α]D27 +94.6 (c. 0.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 8.77 (d, J=9.0 Hz, 1H, ArH4″); 8.71 (d, J=8.1 Hz, 1H, ArH3″); 7.89 (m, 2H, ArH1″ and ArH10″); 7.61 (m, 5H, ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.48 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.26 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′); 6.25 (d, J=7.5 Hz, 1H, NH); 5.00 (m, 1H, H2); 3.79 (s, 3H, OCH3); 3.30 (dd, J=5.7, 13.8 Hz, 1H, H3a); 3.20 (dd, J=6.0, 13.8 Hz, 1H, H3b); 2.05 (s, 3H, COCH3). Mass Spectrum (CI, +ve) m/z 398 (100%) [MH+]. HRMS (EI) calcd for C26H23NO3 397.1678, found 397.1680.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)Cl.[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([O-:37])=[O:36]>O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:9]([OH:16])[CH2:10][N:11]([S:44]([C:41]1[CH:40]=[CH:39][C:38]([N+:35]([O-:37])=[O:36])=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 42.5 °C
Yield: 93.5 %

Procedure:
[(1S,2R)-3-[(2-methylpropyl)amino]-2-hydroxy-1-(phenyl methyl)propyl]carbamic acid tert-butyl ester (4, 100 gm) and triethylamine (39.04 g) was added to methylenedichloride (1200 mL) and the temperature was raised to 40° C. p-nitro benzene sulfonyl chloride solution (72.3 g of p-NBSC dissolve in 300 mL methylenedichloride) was added slowly at 40-45° C. for 2-3 hrs. The reaction was maintained for 3 hours at 40-45° C. After completion of the reaction, water (500 mL) was added, separated the organic layer and distilled out methylene dichloride at atmospheric pressure. Finally, strip out the methylene dichloride by using isopropyl alcohol (200 mL). Isopropyl alcohol (1000 mL) was added to the distillate and maintained the stirring for 60 minutes at 70-80° C. Cooled the mass to 30-35° C., filtered and washed with Isopropyl alcohol to get title compound 3 (yield 145 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[CH:16][CH:17]=2)[S:9][C:10]=1[CH3:11])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[N:14]=[CH:13][C:12]([C:8]2[S:9][C:10]([CH3:11])=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(-c3ccccc3F)nc2)sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(-c3ccccc3F)nc2)nc1CCO
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of {2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-acetic acid ethyl ester (1.7 g, 4.77 mmol) in THF (10 mL) is added LiAlH4 (1.0 M in THF, 4.8 mL, 4.8 mmol) at 0-5° C., and then stirred for 2 h. The reaction is then quenched by water and 5 N NaOH, diluted with THF and filtered through a pad of celite. The filtrate is concentrated and purified by column yielding 1.4 g of the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]1OC(O)C[O:35][CH:34]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH2:33][CH2:34][OH:35])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: OC1COC(O)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(C/C=C/c3cccc(C#N)c3)CCO)cc2)CC1
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and glycolaldehyde dimer (277 mg) in dichloromethane (20 ml) were added acetic acid (0.13 ml) and sodium cyanoborohydride (72 mg) in an ice bath. The mixture was stirred at the same temperature for 5 hours and then at room temperature for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/3 as an eluant to give the desired compound (1100 mg, yield 50%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(Cl)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1Cl
Yield: 30.4 %

Procedure:
A mixture of 2-chloro-5-methylbenzonitrile (10.6 g, 69.9 mmol), N-bromosuccinimide (12.2 g, 68.5 mmol), and dibenzoyl peroxide (349 mg, 1.44 mmol) in benzene (350 ml) was refluxed 1.5 hours, cooled, and evaporated to dryness under vacuum. The residue was suspended in 7:3 (v/v) hexane-dichloromethane, filtered, and evaporated. The crude product was chromatographed on silica gel (650 g) eluted with 7:3 (v/v) hexane-dichloromethane to provide 4.8 g (30%) 4-chloro-3-cyanobenzyl bromide, m.p. 55°-58° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)[N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10]3>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10]3
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@H](O)C=C12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Reaction time: 3.5 h

Procedure:
A solution of 17β-Hydroxymethyl-3b-hydroxy-6-t-butoxycarbonyl-6-azaandrost-4-ene (prepared as described in Example 5 above), in chloroform (250 mL) is treated with activated manganese(IV) oxide. After stirring 3.5 h, the manganese salts are removed by filtration through Celite. The solution is concentrated and chromatographed on silica gel (50% ethyl acetate/hexanes) to give 17β-hydroxymethyl-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one of sufficient purity to carry on to subsequent steps; yield 9.75 g (98%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[N:16]=[C:17]([C:24]#[N:25])[C:18]([C:22]#[N:23])=[N:19][C:20]=1Cl>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:20]2[C:15]([Cl:14])=[N:16][C:17]([C:24]#[N:25])=[C:18]([C:22]#[N:23])[N:19]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2Cl)CC1
Temperature: -45 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
To a solution of 1-Boc-piperazine (8 mmol, 1.5 g) and anhydrous tetrahydrofuran cooled at −45° C. was added 5,6-dichloro-2,3-dicyanopyrazine (4 mmol, 800 mg). The mixture was stirred at −45° C. for 1.5 hours. Reaction mixture was concentrated and stirred in EtOAc, filtered and concentrated. The crude material was purified on silica column using 30% EtOAc/hexanes to yield 3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (640 mg).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][N:5]([C:7](=[O:38])[C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]3[CH2:36][CH2:35]3)[CH2:26][CH2:25]2)=[O:23])=[CH:10][C:9]=1[Cl:37])[CH3:6].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:37][C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]3[CH2:35][CH2:36]3)[CH2:26][CH2:25]2)=[O:23])[C:12]([Cl:14])=[CH:13][C:8]=1[C:7]([N:5]([CH2:4][C:3]([OH:39])=[O:2])[CH3:6])=[O:38]
Reactant: COC(=O)CN(C)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 0.057 g (0.10 mmol) ({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-acetic acid methyl ester (Example 31) in 1 mL dioxane and 1 mL water was added 0.005 g (0.12 mmol) lithium hydroxide monohydrate. After stirring at room temperature for 2 hours, dioxane was removed by evaporation. The pH of the formed yellow solution was adjusted to 1 with 1M aqueous hydrochloric acid. The aqueous solution was saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give 0.053 g (95%) of the title compound as a yellow solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:1]1([C:7](=[O:9])[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCCCC1
Reactant: CC(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)CC(=O)C1CCCCC1

Procedure:
Using ethyl cyclohexane carboxylate (63 g, 0.4 mol) and 4-phenyl-2-butanone (20 g, 0.13 mol), the reaction was carried out in the same manner as described in Example 2, (1) and crude dark orange oil (23 g) was chromatographed on silica gel (Wako Gel C-200) eluting with n-hexane/ethyl acetate (100:1→100:2→100:3) to afford the title compound as a yellow oil which was an ca 3:17 mixture of Keto/Enol by the methylene singlet at δ3.55 ppm and the methine singlet at δ5.45 ppm in the 1HNMR spectrum; yield: 2.5 g.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-nitropyridin-2-yl)cyclobutane-1,3-diamine (580 mg, 1.699 mmol), ammonium chloride (46 mg, 0.849 mmol) and iron dust (0.036 mL, 5.10 mmol) were suspended in a mixture of water (1.000 mL) and ethanol (3 mL). The reaction mixture was stirred at 50° C. for 16 hours then cooled and partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was dried with sodium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave N2-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (370 mg, 1.188 mmol, 69.9% yield) as light-yellow solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:15][C:9]1[CH:10]=[CH:11][C:12]([OH:14])=[N:13][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)nc1NC1CCCCC1

Procedure:
6-(Cyclohexylamino)-5-nitropyridin-2-ol (0.2 g, 0.843 mmol) was dissolved in methanol (168 mL). Palladium (5% Pd/C, 145 mg, 0.0063 mmol) was added. The reaction was flushed with nitrogen and stirred under a balloon filled with hydrogen for 3 h at room temperature. The reaction was monitored by TLC until the starting materials were consumed. The mixture was filtered through Celite® and concentrated to give the title compound as a dark green solid which was used immediately in next step without further purification.
Reaction SMILES: O=O.[O:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][C:6]([O:8][CH3:9])=[O:7].CO>ClCCl>[OH:3][C@H:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCCCCCCCC(=O)CC(=O)OC
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reaction time: 19 h
Yield: 98.5 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 46.2 g (180 mmol) of methyl 3-oxotetradecanoate, 131 ml of methanol and a solution of 2.1 mg (0.0036 mmol) of (R)-MeOBIPHEP and 1.08 mg (0.0018 mmol) of Ru2Cl4 (COD)2 (CH3CN) [Lit.: E. Singleton et al., S. Afr. Tydskr. Chem. 40, 183 (1987)] in 5 ml of dichloromethane. The hydrogenation was effected at 80° C. and 35 bar. The conversion amounted to >99% after 19 hours. The hydrogenation solution was concentrated at 50° C./17 mbar and the crystalline residue was taken up in 500 ml of diethyl ether. In order to separate the catalyst, the ethereal solution was filtered over 100 g of silica gel; e.e.=97.1%. After concentrating and drying the filtered ethereal phase there were obtained 45.8 g of methyl (R)-3-hydroxytetradecanoate as white crystals; e.e.=97.1%. After recrystallization from n-hexane there were obtained 41.9 g of pure methyl (R)-3-hydroxytetradecanoate; m.p. 42°-43° C.; e.e. 99.8%; [α]D20 : -16.4° (c=3.8, CCl4).