Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@:24]([CH3:29])([CH:26]1[CH2:28][CH2:27]1)[OH:25]>>[CH:26]1([C@:24]([OH:25])([CH3:29])[CH2:23][NH:22][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Reactant: C[C@](O)(CN)C1CC1
Product: C[C@](O)(CNC(=O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluorophenyl)-6-cyclopropylmethoxy-nicotinic acid and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (10 g) in ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon (5 g, 50% wet) at ordinary temperature under atmospheric pressure. After the absorption of hydrogen has ceased, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield ethyl 6-(4-piperidyl)hexanoate. This ester is dissolved in a mixture of water (100 ml), ethyl acetate (200 ml) and sodium bicarbonate (10 g). Benzyloxycarbonyl chloride (7.2 ml) is added dropwise at room temperature and the resulting mixture is stirred overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluent to give ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.7 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].CC[C:20](OCC)=[S:21].[C:25]([O:29]Cl)(C)(C)[CH3:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:17][C:14]1[CH:15]=[C:16]2[C:2](=[C:3]([C:4](=[O:5])[C:6]3[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=3)[CH:13]=1)[NH:1][C:25](=[O:29])[CH:26]2[S:21][CH3:20]
Reactant: CCOC(=S)CC
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc(F)cc1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2c(C(=O)c3ccc(F)cc3)cc(F)cc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of 46.6 g (0.2 mole) of 2-amino-4',5-difluorobenzophenone in 1300 ml of methylene chloride was cooled to -65° C. and 26.8 g (0.2 mole) of ethyl methylthioacetate was added. The cold mixture was stirred vigorously while 23.0 g (0.2 mole) of 95% tertiary butoxy chloride was added dropwise. The mixture was stirred at -70° C. for one hour, then 23 g (0.22 mole) of triethylamine was added. The mixture was allowed to warm to room temperature and 10 ml of concentrated hydrochloric acid was added. The mixture was heated at reflux with vigorous stirring for 2 hrs. The organic phase was separated and the residue was crystallized from ethyl acetate to give 28.9 g (45%) of the titled compound as off-white crystals, m.p. 171.0°-172.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[Br:1][C:2]1[C:3]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 90 °C
Yield: 96.4 %

Procedure:
The product from Example 13A (0.578 g, 1.26 mmol), iron (0.352 g, 6.31 mmol), and ammonium chloride (0.101 g, 1.89 mmol) were combined in a mixture of tetrahydrofuran (9 mL), ethanol (9 mL), water (3 mL) and heated at 90° C. for 2 hours. The mixture was cooled, filtered through Celite and the Celite pad was washed repeatedly with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.52 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11]C(OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH2:25])[CH:20]=[CH:21][CH:22]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][NH:25][CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1cccc(CCN)c1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Solvent: CO
Product: COc1ccc(CNCCc2cccc(C)c2)cc1OC
Yield: 74 %

Procedure:
A solution of methyl 3,4-dimethoxyphenylacetate (18.5 g, 0.088 mole) and 2-(3-methylphenyl) ethylamine was heated at 180° for 1 h. The crude amide was dissolved in 50 ml of methanol and precipitated as fine needles with 150 ml of hexane to give the title compound (20.4 g, 74%). The mother liquor deposited more material which was recrystallized from toluene (charcoal) to give an additional 4.7 g (17%) of amide. The total yield of N-(3,4-dimethoxyphenylacetyl)-2-(3-methylphenyl) ethylamine, mp 101°-102°, was 91%.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:10]1([S:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:37][C:38]([F:44])([F:43])[S:39]([OH:42])(=[O:41])=[O:40]>CCCCCC>[F:37][C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40].[C:18]1([S+:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:9])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=S(c1ccccc1)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Product: Cc1cc(C)c([S+](c2ccccc2)c2ccccc2)c(C)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 5 °C
Yield: 84.3 %

Procedure:
In 36.1 g (0.3 mole) of mesitylene was dissolved 6.1 g (0.03 mole) of diphenylsulfoxide, and 12.6 g (0.06 mole) of trifluoroacetic anhydride was poured thereinto under cooling at 5° C. or lower and further 4.5 g (0.03 mole) of trifluoromethane sulfonic acid was added dropwise thereto at −5 to 5° C., followed by allowing a reaction to take place at the same temperature for 2 hours with stirring. Into the resultant was poured 20 ml of n-hexane, followed by separation. This process step series was conducted three times and the resulting crude oily substance was crystallized from a mixture of butyl acetate and isopropyl ether and the crystal was recovered by filtration and dried to give 11.5 g (Yield: 84%) of diphenyl-2,4,6-trimethylphenylsulfonium trifluoromethanesulfonate as white crystal.
Reaction SMILES: [C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH:7]=[CH:6]2)(=[O:3])[CH3:2].[H][H]>C(O)C>[C:1]([C:4]1[CH:5]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]([CH2:9][C:10]=1[CH3:11])[CH2:7][CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)CC2C=CC1N2C(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CCO
Product: CC(=O)C1=C(C)CC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
A solution of 2-acetyl-3-methyl-8-(tert-butyloxycarbonyl)-8-azabicyclo [3.2.1]oct-2,6-diene (0.74 g, 2.81 mmol) and RhCl(PPh3)3 (0.026 g, 0.028 mmol) in 50 ml ethanol was pressurized with 45 psi hydrogen gas and shaken for about 12 hours. The solvent was then evaporated and the residue was purified by silica gel column chromatography (using 3 parts diethyl ether and 7 parts petroleum ether) to give 2-acetyl-3- methyl-8-(tert-butyloxycarbonyl)-8-azabicyclo [3.2.1]oct-2-en.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[C:8]([S:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)Cl.CC(O)C>O1CCCC1.Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8]([S:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:7][N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:13]=1
Reactant: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.46 g (6.76 mmole) of 3 -n- butyl-5-(carbomethoxymethylthio)-4-(4-nitrobenzyl)-4H-1,2,4-triazole in 32 ml of tetrahydrofuran stirred in an ice bath was added gradually over 15 minutes a solution of 15.2 g (67.6 mmole) of stannous chloride dihydrate in 19 ml of concentrated HCl. The ice bath was removed, and the mixture was stirred at room temperature for 1.5 hours. It was then poured into a vigrously stirred mixture of 68 ml of 50% NaOH and 270 g. of ice. This was rapidly extracted with 3×300 ml of ether. The combined ether extracts were washed with 150 ml of H2O, then dried (MgSO4), filtered, and concentrated to give 566 mg (25%) of a white waxy solid, homogeneous by TLC in 97:3 CHCl3 -iPrOH; mass spectrum (FAB) m/e 335 (M+1)+. This material was used directly in the next reaction.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH3:12][O:13][CH2:14][CH2:15][OH:16]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:6][CH2:7][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH2:3][O:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: ClCCN(CCCl)CCCl
Reactant: COCCO
Agent: Cl
Product: COCCOCCN(CCOCCOC)CCOCCOC

Procedure:
51.6 g (namely, 0.215 mol) of tris-(2-chloroethyl)-amine hydrochloride were added to the above mixture. The mixture was subsequently heated at the reflux temperature of the 2-methoxyethanol (125° C.) for 12 hours and the solvent was then distilled under reduced pressure. The excess sodium 2-methoxyethanolate was neutralized by adding 11.6 cm3 of aqueous HCl (10 N). The sodium chloride was filtered off and the solution was distilled.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Brc1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 35 mg (0.05 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 8), 1.57 g (10.0 mmol) of bromobenzene, 1.02 g (12.0 mmol) of piperidine and 1.35 g (14.0 mmol) of NaO(t-Bu) in 20.0 mL of toluene. The resulting mixture was refluxed for 5 h before the reaction was cooled to room temperature and quenched with 50 mL of H2O. The mixture was transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×30 mL), brine (30 mL), and dried over mgSO4, filtered, and the ether removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel with hexane/ethyl acetate (50:1 volume ratio). The eluate was concentrated by rotary evaporation followed by high vacuum to give 670 mg (42% yield) of 1-phenylpiperidine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=4[N:19]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2>C(#N)C.CN(C)C=O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][N:28]([C:17]1[C:18]3[N:19]=[C:10]([C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=1)[CH2:27][CH2:26]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=c1[nH]cnc2ccc(-c3cnc4[nH]ccc4c3)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc2c(cc1OC)CN(c1ncnc3ccc(-c4cnc5[nH]ccc5c4)nc13)CC2
Temperature: 60 °C
Yield: 51 %

Procedure:
0.20 g of 6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and 0.22 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are suspended in 10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate, 255 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are subsequently added, and the mixture is heated at 60° C. under nitrogen until the reaction has proceeded to completion (HPLC check, about 5 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.17 g of 4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine (“A7”) as white solid (yield 50%, content 97%); MS-FAB (M+H+)=439; Rf (polar method): 1.68 min;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:12]=[CH:11][C:9]2[NH:10][CH:22]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:26]3[CH2:27][CH2:28][CH2:29][O:24][CH:25]3[C:8]=2[CH:7]=1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: C1=COCCC1
Reactant: O=CC1CCCCC1
Solvent: CC#N
Product: Clc1cccc(Oc2ccc3c(c2)C2OCCCC2C(C2CCCCC2)N3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a solution of 4-(3-chlorophenoxy)aniline (220 mg, 1 mmol, 1 equiv.) in dry MeCN (3 mL) under argon atmosphere was added cyclohexanecarbaldehyde (121 μL, 1 mmol, 1 equiv.) and 3,4-dihydro-2H-pyran (90 μL, 1 mmol, 1 equiv.) sequentially, followed by Mg(ClO4)2 (12.3 mg, 0.05 mmol, 0.05 equiv.). The reaction mixture was stirred at r.t. overnight. The solvent was removed under reduced pressure and the residue taken up in CH2Cl2 and passed through Decalite. The solvent of the filtrate was removed under reduced pressure and the crude crystallized from AcOEt to afford pure cis diastereomer (4aSR*,5RS*,10bSR*)-9-(3-chlorophenoxy)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (138 mg, 34%) as white solid. The solvent from the mother liquid was evaporated and the remaining residue purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt up to 10%) to obtain additionally 144 mg of the cis diastereomer (overall yield cis 71%) along with the 78 mg of trans diastereomer (4aSR*,5SR*,10bSR*)-9-(3-chlorophenoxy)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c] (18%) as yellow oil. The corresponding hydrochloride salts of the cis and trans diastereomer were prepared as follows.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl-:15].[Cl:15][CH2:11][C:3]1[CH:2]=[NH+:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCc1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1c[nH+]c2ccccc2c1
Product: [Cl-]

Procedure:
3-Quinolinylmethanol (that prepared step (i) above) was dissolved in DCM (2 mL) and SOCl2 (5 mL) was added (dropwise initially) to the solution, which was then refluxed for 1 h. The DCM and excess SOCl2 were then removed under reduced pressure to yield the sub-title compound, which was employed directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1.[Si:35]([O:42][C@H:43]1[CH2:52][C@H:51](O)[C@H:50]2[C:45]([CH:46]=[CH:47][C@H:48]([CH3:71])[C@@H:49]2[CH2:54][CH2:55][C@H:56]2[O:61][C:60](=[O:62])[CH2:59][C@H:58]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[CH2:57]2)=[CH:44]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C(Cl)Cl>[Si:35]([O:42][C@H:43]1[CH2:52][C@H:51]([O:5][C:4](=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[C@H:50]2[C:45]([CH:46]=[CH:47][C@H:48]([CH3:71])[C@@H:49]2[CH2:54][CH2:55][C@H:56]2[O:61][C:60](=[O:62])[CH2:59][C@H:58]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:65])[CH3:66])[CH2:57]2)=[CH:44]1)([C:38]([CH3:39])([CH3:40])[CH3:41])([CH3:37])[CH3:36]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)CC(C)(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
0.46 ml (3.6 mmol) of 3,3-dimethylbutyric acid, 741 mg (3.6 mmol) of dicyclohexyl carbodiimide and 13 mg (0.09 mmol) of 4-(1-pyrrolidinyl)pyridine were added to a solution of 1.00 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 15 ml of methylene chloride, whilst ice-cooling. The resulting mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for a further 19 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the resulting residue was mixed with 20 ml of diethyl ether. Any insoluble material was removed by filtration and then washed twice with diethyl ether, using 5 ml for each washing. The filtrate and the washings were then combined and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 555 mg (47% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30](Cl)=[O:31].O>C(#N)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][C:30]([NH:20][C:12]1([C:10]([O:9][CH3:8])=[O:11])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:31]
Reactant: COC(=O)C1(N)CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.6 %

Procedure:
To 5.4 g of potassium carbonate and 2 g of 4-Amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride in 10 ml of acetonitrile, 1.94 g of (2,5-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile are added at a temperature of 0-5° C. After stirring for 22 h at room temperature the reaction mixture is poored on cold water and extracted with ethyl-acetate. The organic phase is dried over sodium sulfate, filtered and evaporated to yield 2.13 g of methyl 4-[2-(2,5-dimethyl-phenyl)acetylamino]-1-methoxy-piperidine-4-carboxylate as beige cristalline solid. 1H-NMR (CDCl3): □ 1.95-2.30 (br signals, total 4H), 2.27 (s, 3H), 2.33 (s, 3H), 2.77-3.23 (br signals, total 4H), 3.48 (s, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 5.40 (br s, 1H), 7.02 (s, 1H), 7.04 (d, 1H), 7.11 (d, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:15]>[Ni]>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(CC2CCCCC2)CC1
Reactant: N
Agent: [Ni]
Product: NC1CCN(CC2CCCCC2)CC1
Reaction time: 3.5 h

Procedure:
A solution of 1-cyclohexylmethylpiperid-4-one (65 g; 0.33 moles in a saturated ethanolic solution of ammonia (350 ml) was hydrogenated in the presence of Raney nickel catalyst (6.5 g) at 75° C. and 13 atmospheres for 3.5 hours. The mixture was cooled, the catalyst filtered off and the solvent removed by distillation in vacuo. The residue was treated with a saturated ethanolic solution of hydrogen chloride, and the insoluble dihydrochloride was filtered off, treated with an aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried (Na2SO4) and the solvent removed in vacuo giving 1-cyclohexylmethyl-4-aminopiperidine (45.5 g) as a viscous liquid, b.p. 105°-110° C./0.3 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(O)(=O)C>[N:12]1([C:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCCC1
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CCCCC2)nc1

Procedure:
Crude 5-nitro-2-(piperidin-1-ylcarbonyl)pyridine was reduced by hydrogen under atmospheric pressure in the presence of 10% paladium on carbon (4 g) in acetic acid (500 mL). The catalyst was separated by filtration and the solvent evaporated in vacuum to give crude 6-(piperidin-1-ylcarbonyl)pyridin-3-amine, which was used for the next stage without additional purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9]>>[CH2:8]([S:10]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)CCN
Product: CCS(=O)(=O)NCCC(=O)OC

Procedure:
N-(ethylsulfonyl)-β-alanine, methyl ester (21) was prepared from methyl β-alaninate and ethanesulfonyl chloride on a 32 mmol scale in the manner described in Example 13 above to yield 1.53 g (24%) of product. Analysis calculated for C6H13NO4S. 0.25 H2O (M.W. 199.74): C, 36.08; H, 6.81; N, 7.01; S, 16.05. Found: C, 36.03; H, 6.82; N, 6.97; S, 15.59.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[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(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
An ice cold solution of N-benzyloxycarbonyl-4-hydroxymethylpiperidine (2.5 g, 10 mmol) in 100 mL CH2Cl2 is treated with pyridinium chlorochromate (3.23 g, 15 mmol). The reaction is stirred at ambient temperature for 3 hours. The mixture was diluted with 100 mL Et2O and filtered through a plug of silica. The filtrate was concentrated in vacuo to provide 2.3 g of the title compound as a pale green liquid.