Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1)[NH2:5].O=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:26]2[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Reactant: O=C1CC(C(=O)O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200 mg, 0.549 mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg, 0.549 mmol) in methanol (1280 μl) at room temperature was added acetic acid (842 μl, 14.72 mmol). The reaction mixture was stirred at room temperature for 10 minutes before addition of sodium cyanoborohydride (17.25 mg, 0.275 mmol) as a single portion. The reaction mixture was stirred at room temperature overnight. LCMS (2007—9476) indicated a 43% by ELSD (2.90 min)s conversion to (M+H) 462.16. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (135 mg, 0.292 mmol, 53.2% yield) as a white solid. LCMS (Table A, Method b) indicated 100% by UV (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:21])[C@@H:10]([CH3:20])[O:11][C:12]1[C:17](I)=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[Cl-].[Na+]>CN1C(=O)CCC1.C1COCC1.[Cu]I>[CH2:1]([O:8][C@H:9]([CH3:21])[C@@H:10]([CH3:20])[O:11][C:12]1[C:17]([C:25]([F:27])([F:26])[F:24])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [Cl-]
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 54 %

Procedure:
A solution of 4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-iodopyrimidine in NMP and THF was admixed at room temperature with stirring with copper(I) iodide, potassium fluoride and (trifluoromethyl)trimethylsilane. The mixture was stirred for 5.5 hours at 80° C. After cooling, the mixture was added to dilute sodium chloride solution and extracted with acetic ester (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 54%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][S:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (5.0 gm, 1.0 eq, 40.98 mmol), anhydrous K2CO3 (17 g, 3 eq, 123 mmol), and methanesulfonylchloride (4.76 mL, 1.5 eq, 61.37 mmol) in dry DMF (200 mL) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. Organic layer was dried (Na2SO4), condensed, and the residue obtained was chromatographed using ethyl acetate and hexanes to obtain the title compound as white solid (2.0 g, 25%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCNC4)c3)n2)cc1

Procedure:
Intermediate 8b was coupled with tyramine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 376. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 7.0-7.5 (m, 4H) 6.9 (d, 1H) 6.68 (d, 2H) 5.05 (m, 1H) 4.28 (m, 1H) 3.8 (m, 2H) 3.2-3.6 (m, 4H) 2.9 (m, 2H) 2.0-2.6 (m, 2H).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[F:22])C1C=CC=CC=1.Cl>CCO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](F)C1
Reaction time: 14 h
Yield: 53 %

Procedure:
To a solution of the enantiomeric mixture of cis-4-benzylamino-1-tert-butoxycarbonyl-3-fluoropiperidine (prepared according to the procedures of J. Med. Chem. 1999, 42, 2087-2104, 1.0 g, 3.2 mmole) in EtOH (40 mL) was added 3 N HCl (2.5 L) and 10% Pd/C (50 mg). The reaction was shaken under H2 (40 psi) on a Parr apparatus for 14 h, then was filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3) to afford the title compound (370 mg, 53%) as a white solid.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[O:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[O:26][CH2:11][CH2:10]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCO2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-[5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl]propiolate (Compound A) but instead using 1.86 g (10 mmols) of [4,4-dimethyl-chroman-6-yl]ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyllithium the title compound was obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[CH:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[NH:5]1.I[CH2:33][C:34]#[N:35]>C(#N)C>[C:34]([CH2:33][N:5]1[CH:6]([C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][C:8]=2[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:4]1=[O:3])#[N:35]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.29 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 96 μmol) in acetonitrile (3.0 mL). After 20 min, 2-iodoacetonitrile (7 μL, 0.1 mmol) is added. The mixture is stirred at room temperature over night and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 11 mg; ESI mass spectrum [M+H]+=437; Retention time HPLC: 0.63 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10](OCC)OCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[S:8][CH:9]=[CH:10][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CSc1ccccc1Cl)OCC
Solvent: Cc1ccccc1
Product: Clc1cccc2ccsc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 1-chloro-2-(2,2-diethoxyethylsulfanyl)benzene (3.95 g, 15.14 mmol) in toluene (40 mL) was added polyphosphoric acid (15 g, 137.5 mmol). The mixture was heated at reflux for 4 h. then was poured in to ice water, stirred for 30 min and extracted with toluene. The combined toluene extracts were washed with aqueous sodium bicarbonate followed by brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with hexane to afford pure 7-chlorobenzo[b]thiophene (1.72 g, 67.5%). 1H NMR (400 MHz, CDCl3) δ=7.13-7.30 (m, 3H), 7.38 (d, J=5.31 Hz, 1H), 7.62 (dd, J=7.33, 1.52 Hz, 1H); MS (ES+): m/z 169.06 [MH+].
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([F:14])[CH:10]=[C:11]([Br:13])[CH:12]=1.C1C[O:18][CH2:17]C1>>[Br:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([F:14])[CH:10]=1)[CH:17]=[O:18]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Product: O=Cc1cc(F)cc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
step 1—To a solution of iso-propylmagnesium chloride in THF (500 mL of a 2M solution in THF, 1.0 mol) and THF (200 mL) was added a solution of 3,5-dibromofluorobenzene (25; 200 g, 0.79 mol) in THF (100 mL) while maintaining the temperature at ca. 0 C. After rinsing with THF (3×20 mL) the mixture was aged for 2 h at ca. 0° C. and then warmed to ca. 20° C. and aged for 0.5 h. The reaction was sampled by HPLC and then cooled to ca. 0° C. DMF was added over 0.5 h while maintaining the temperature at ca. 0° C. The mixture was aged 1.5 h at ca. 0° C. and then warmed slowly to ca. 20° C. overnight. After sampling by HPLC, the mixture was diluted with heptane (200 mL) and then with a mixture of con HCl (120 mL) diluted to 360 mL with water. Con HCl (50 mL) was added to adjust the pH to <7. The organic phase was separated, washed with water (400 mL) and evaporated to dryness to afford 160.8 g (100.5%) of 28 as a yellow oil which solidified on standing.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[CH3:3][C:2]1([CH3:10])[CH2:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:15]2[CH:16]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]1=2
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 2,5-dichloro-2,5-dimethyl-hexane (Intermediate 1, 97 g, 0.53 mol) and phenol (50 g, 0.53 mol) in CHCl3 (500 mL) at 0° C. was added AlCl3 (71 g, 0.54 mmol) portionwise. After stirring for 2 h at 0° C., the mixture was poured onto ice and was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Recrystallization of the resulting solid from Et2O-hexane (1:1) gave the title compound as off-white crystals (95.7 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Reactant: O=S(=O)(O)Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced in portions into chlorosulfonic acid (6.6 ml). The mixture was subsequently stirred at 40° C. for one hour. The reaction mixture was then cooled to room temperature and an ice/water mixture was added. The precipitate which separated out during this was filtered off with suction and taken up in ethyl acetate which, after washing with saturated brine was dried over magnesium sulfate. Subsequent concentration afforded 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonyl chloride as a solid crude product, a portion of which (150 mg) was directly introduced in portions into dimethylamine solution (5 ml, approx. 40% in water) cooled to 10° C. The resulting suspension was subsequently stirred at this temperature for 1.5 h. Then ice-water was added and, after extraction three times with ethyl acetate, the combined ethyl acetate phases were washed with saturated brine and dried over magnesium sulfate. The residue was taken up with water and, after addition of 2 N HCl, freeze dried. The crude product obtained in this way was then purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=2[Cl:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1Cl
Product: Fc1cccc(-c2cncc(Br)c2)c1Cl

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 3,5-dibromo-pyridine and 2-chloro-3-fluoro-phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:17](N1CCCCC1)=[O:18].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:17]=[O:18])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=CN1CCCCC1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 2,4-dichloropyridine (10 g) in THF (100 mL) was added dropwise lithium diisopropylamide solution (2M, 37 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hr. To the reaction mixture was added dropwise 1-formylpiperidine (7.7 g) at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. The reaction mixture was added to 10% aqueous acetic acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (7.0 g).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:7][CH:8]=1
Reactant: OCc1cnc(-c2cccc(C(F)(F)F)c2)nc1C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ncc(CCl)c(C3CC3)n2)c1

Procedure:
0.300 g (1.019 mmol) of the above prepared [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol was dissolved in 5 ml of CH2Cl2 and treated at 0° C. with 0.15 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at ambient temperature for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents gave 0.315 g of pure title compound as white solid of mp. 92–95° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)NCC(=O)OC

Procedure:
3.36 g of Z-Ile-Gly-OMe are dissolved in 100 ml of methanol and 10 ml of 1 N hydrochloric acid and hydrogenated in the presence of 0.5 g of Pd on charcoal (10 %). After filtering off the catalyst the solvent is completely evaporated. The resulting foam is homogeneous in a thin layer chromatogram on silica gel; Rf = 0.26 in chloroform-methanol (95:5).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 11) (50 mg, 200 μmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 9.6 mg, 220 μmol) and after ½ h with methyl iodide (13.7 μL, 220 μmol) in DMF (0.2 mL). After stirring 1 h at 0° C. and 1.5 h at room temperature, the reaction mixture was poured on aq. sat. NaHCO3 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH 1%). Precipitation from CH2Cl2 with n-pentane gave the title compound (17 mg, 32%) as off-white powder. MS: 265.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20]>[Pd].C(O)(=O)C>[ClH:20].[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reaction time: 96 h

Procedure:
A mixture of 62.69 g (0.256 mole) of diphenyl-4-pyridylmethane and 6.4 g of 10% palladium on carbon (0.0060 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 85° for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanolacetronitrile, and excess ethereal hydrogen chloride was added. A precipitated was collected to give 59.13 g (80.3%) of slightly impure title compound as a white crystalline solid, m.p. 273°-274° C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, m.p. 275.5°-277° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[NH:8][C:7]([S:11][CH2:12][C:13]3[N:14]=[C:15]([CH3:18])[S:16][CH:17]=3)=[N:6][C:5]=2[N:19]=1.P(Cl)(Cl)([Cl:22])=O>CN(C)C1C=CC=CC=1>[Cl:22][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)[N:8]=1
Reactant: Cc1nc(CSc2nc3nc(N)sc3c(=O)[nH]2)cs1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(CSc2nc(Cl)c3sc(N)nc3n2)cs1

Procedure:
The product from step (b), (8.7 g), was suspended in phosphorus oxychloride (88 ml) and dimethylaniline (8.8 ml). The mixture was heated under reflux for 2 hrs then evaporated. The residue was stirred in hot water, cooled and the pH adjusted with sodium hydroxide solution to pH5. The solid was collected, washed with water and dried. Chromatography (SiO2, methanol/dichloromethane as eluant) gave the sub-title compound (4.3 g)
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])CCC[CH2:3][CH2:2]1.BrCCBr.ICCC.C([Cu])#N.[Li+].[Cl-].CC1(C)N([O])C(C)(C)CC(=O)C1>[Zn].C[Si](C)(C)Cl>[CH2:1]([O:7][N:8]1[C:9]([CH3:18])([CH3:17])[CH2:10][C:11](=[O:16])[CH2:12][C:13]1([CH3:14])[CH3:15])[CH2:2][CH3:3]
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: N#C[Cu]
Agent: CC1(C)CC(=O)CC(C)(C)N1[O]
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Solvent: CCCI
Product: CCCON1C(C)(C)CC(=O)CC1(C)C
Yield: 26 %

Procedure:
N-Propoxy-4-oxo-2,2,6,6-tetramethylpiperidine (3.2 g, 26%) is synthesized in the same manner as described above with regard to N-cyclohexyloxy-4-oxo-2,2,6,6-tetramethylpiperidine, with the exception of the addition of Zn (61.1 mmol, 4.00 g), 1,2-dibromoethane (200 μl), trimethyl-chlorosilane (250 μl), iodopropane (58.8 mmol, 10.0 g), CuCN (53.6 mmol, 4.80 g), LiCl (114 mmol, 4.80 g) and 4-oxo-TEMPO (58.8 mmol, 10.0 g). 1H-NMR (CDCl3): δ=3.78 (t, J=6.7 Hz, 2H, O—CH2), 2.55 (d, J=12.7 Hz, 2H, CH2—CCH3), 2.20 (d, J=12.7 Hz, 2H, CH2—CCH3), 1.57 (m, 2H, CH2—CH3), 1.28 (s, 6H, C—CH3), 1.14 (s, 6H, C—CH3), 0.95 (t, J=7.45 Hz, 3H, CH2—CH3); 13C-NMR (CDCl3): δ208.5, 78.5, 63.0, 53.3, 32.5, 22.5, 21.8, 10.9.
Reaction SMILES: C(C1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16]C=CC=3)[CH2:14][C@@H:13]2O)=[N:5]C(CC)=CN=1)C.Br[C:23]1[C:28]([CH2:29][CH3:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])=[C:25]([CH2:39][CH3:40])[N:24]=1.CC1C=C(C)N=C(N)C=1>>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:26]1[N:27]=[C:28]([CH2:29][CH3:30])[C:23]([NH:5][C:4]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:12]([CH3:13])[N:11]=2)=[N:24][C:25]=1[CH2:39][CH3:40]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: Cc1cc(C)nc(N)c1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Nc1cc(C)cc(C)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and 4,6-dimethylpyridin-2-amine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.31, 1.38, 2.37, 2.46, 2.62, 2.90, 6.68, 7.31, 7.37, 7.52, 8.28; HRMS (ESI+) Calcd for C21H22Cl2N4 (M+H)+ 401.1299, found 401.1317.
Reaction SMILES: [CH3:1][C@:2]1([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2N=C(C(F)(F)F)[O:10][N:9]=2)[C:3]1([CH3:18])[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.[C:38](#[N:42])[CH:39]([CH3:41])[CH3:40]>[Cl-].[Cl-].[Zn+2]>[CH:39]([C:38]1[O:10][N:9]=[C:8]([CH2:7][C@@H:4]2[CH2:5][CH2:6][C@@:2]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:1])[C:3]2([CH3:18])[CH3:17])[N:42]=1)([CH3:41])[CH3:40]
Reactant: CC(C)C#N
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Cc2noc(C(F)(F)F)n2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)c1nc(C[C@@H]2CC[C@](C)(NC(=O)OC(C)(C)C)C2(C)C)no1
Temperature: 92.5 °C

Procedure:
To a solution of tert-butyl {(1S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate (prepared in Step-1 example 56) (0.300 g, 1.0 mmoles) in isobutyronitrile (7 mL), ZnCl2 (0.0410 g, 3.0 mmol), PTSA (0.057 g, 3.0 mmol) were added under N2 atmosphere. It was heated to 90-95° C. for six hours. After completion of reaction, isopropyl cyanide was removed under reduced pressure and diluted with water and ethyl acetate. The layers are separated and the organic layer was dried over Na2SO4, and concentrated on a rotavapor. The crude material is purified by column. 0.120 g, Off white sticky mass, 1H NMR (400 MHz, CDCl3) δ ppm: 0.81 (s, 3H), 0.97 (s, 3H), 1.21 (s, 3H), 1.34 (d, 6H), 1.43 (s, 9H), 1.70-1.73 (m, 1H), 1.95-2.00 (m, 2H), 2.22-2.25 (m, 2H), 2.55-2.59 (m, 1H), 2.79-2.83 (m, 1H), 3.17-3.19 (m, 1H), 4.51 (s, 1H). m/z (M−100)+H, 252.2.