Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: CC(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O)C(c1cccc(Br)n1)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-[(6-Bromopyridin-2-yl)methyl]morpholine (Example 45, Step 1) (500 mg, 1.95 mmol) was placed under argon and then taken up in tetrahydrofuran (19.5 mL). The solution was cooled to −78° C. LDA (1.62 mL of 1.8 M, 2.92 mmol) was added dropwise over 30 minutes. The mixture was stirred at −78° C. for one hour. Isobutyraldehyde (0.71 mL, 7.8 mmol) was then added and the reaction was then stirred at −78° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash chromatography (silica, 50-100% ethyl acetate/hexanes) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[C:4]([CH3:9])=[N:3]1.[C:10]([O-])(=[O:12])[CH3:11].[K+].C(OC(=O)C)(=O)C>CCOC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:10](=[O:12])[CH3:11])[C:4]([CH3:9])=[N:3]1
Reactant: CC(=O)[O-]
Reactant: Cc1nn(C)c(C)c1N
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A suspension of 1,3,5-trimethylpyrazol-4-amine (1 g, 7.99 mmol), potassium acetate (0.862 g, 8.79 mmol) and acetic anhydride (0.889 mL, 7.99 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(1,3,5-trimethylpyrazol-4-yl)acetamide (1.390 g, 104%) as a off-white solid. Mass spectrum: MH+ 168
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(O)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(O)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2,6-diamino-4-hydroxypyrimidine (12.9 g, 102.2 mmoles) in 200 ml of a 10% acetic acid solution in water at 80° C. was added dropwise a solution of NaNO2 (7.05 g, 102.2 mmoles) in 20 ml water. A pink precipitate was formed, which was further stirred for 1 hour at 80° C. The reaction mixture was cooled down in the refrigerator overnight. The precipitate was filtered off and dried over P2O5, providing the title compound as a pink powder (15.43 g, yield: 97%). The spectral data are in accordance with literature data (Landauer et al. in J. Chem. Soc. (1953) 3721–3722).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]#[N:18].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:4][N:5]=1)[CH3:16]
Reactant: CCOc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCOc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl) pyrimidine-5-carbonitrile (2.17 g., 9.0 mmole), sodium azide (0.645 g., 9.9 mmole), and ammonium chloride (0.53 g., 9.9 mmole) in dry, N,N-dimethylformamide (18 ml.) was stirred at 125° for 16 hours. The solvent was removed under reduced pressure. The residue was treated with water and the resulting slurry acidified with 1N hydrochloric acid. The mixture was filtered. The collected solid was washed with water, dried, and recrystallized from glacial acetic acid to give the title compound (1.28 g., 50% yield). An analytical sample had m.p. 289°-290° with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)Br.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].CO>C(O)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:25]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reactant: NC(=S)c1ccccc1Cl
Solvent: CO
Solvent: CCO
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone from Step 3 (1.39 g, 4.1 mmol) and 2-chlorothiobenzamide (0.71 g, 4.1 mmol) in 10 mL of ethanol was heated to reflux for 4.4 hours. The solution was cooled to room temperature and poured into 25 mL of methanol, chilled with an ice bath whereupon crystals of pure product formed which were isolated by filtration and air dried to afford the thiazole (1.34 g, 79%): mp 117°-119° C. 1H NMR (CDCl3) 300 MHz 8.37 (m, 1H), 7.62 (m, 2H), 7.49 (d, J=7.7Hz,1H), 7.32 (m, 7H), 7.22 (d, J=8.5Hz, 2H), 2.51 (s, 3H). Mass spectrum M+ +H=412.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH:23]3[NH:26][C:27]3[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=3)[O:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>C(#N)C>[CH2:1]([N:26]([CH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)[CH:25]=2)[CH2:21][CH2:22]1)[C:27]1[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=1)[O:30][CH2:31][C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH3:2]
Reactant: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(c1cccc(OCC(=O)OC(C)C)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Ethyl iodide (45 mg, 0.286 mmol) and potassium carbonate (8 mg, 0.057 mmol) were added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (12 mg, 0.029 mmol) and acetonitrile (2 mL) in a 50 mL round bottom flask at room temperature. The mixture was then heated to reflux and allowed to stir overnight. The solution was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 50% ethyl acetate/hexanes) to afford 7 mg (55%) of isopropyl 2-(3-(ethyl(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH2:6]1)=[O:4].O1CCOCC1.[Cl:28]N1C(=O)CCC1=O>O>[Cl:28][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:7]2[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:20])[F:21])[CH2:6]2)[NH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(N1CCCC(c2cccc3[nH]ccc23)C1)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=C(N1CCCC(c2cccc3[nH]cc(Cl)c23)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 10 g of the product of Step A, 300 ml of dioxane and 5 g of N-chlorosuccinimide was stirred at 20° C. for 20 hours and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water and aqueous sodium chloride solution, was dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 11 g of 3-chloro-4-(1-trifluoroacetyl-piperidin-3-yl)-1H-indole which was used as is for the next step.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1.Cl.C(Cl)[Cl:24].CO>O1CCOCC1>[ClH:24].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2ncc[nH]2)C1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1c[nH]c(C2CCCNC2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 250-mL round-bottomed flask was charged with a solution of benzyl 3-(1H-imidazol-2-yl)piperidine-1-carboxylate (1.5 g, 5.26 mmol, 1.00 equiv) in dioxane (15 mL). To this was added conc. HCl (9 mL). The resulting mixture was stirred for 4 hours at 70° C. in an oil bath. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the resulting solution was diluted with dioxane (10 mL) and concentrated on a rotary evaporator affording 3-(1H-imidazol-2-yl)piperidine hydrochloride as black solid in (0.48 g, 57%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)#[N:2].C[Si]([N:13]=[N+:14]=[N-:15])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([C:1]2[NH:15][N:14]=[N:13][N:2]=2)[N:4]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1nc(C#N)cs1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nnn[nH]2)cs1

Procedure:
A mixture of 4-cyano-2-methylthiazole (5.74 g) (U.S. Pat. No. 4,010,173 1977), trimethylsilyl azide (10.64 g) and dibutyltin oxide (115 g) in toluene (300 ml) was heated at 120° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and extracted with dilute aqueous sodium hydroxide solution. The combined extracts were acidified to pH 5 with 1M HCl and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated. Yield 4.53 g.
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]1OCC[O:10]1)[C:3]2([CH3:15])[CH3:14].CC(C)=O.Cl>O>[CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=[O:10])[C:3]2([CH3:15])[CH3:14]
Reactant: CC1(C)C(CC2OCCO2)CC2CC21C
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)C(CC=O)CC2CC21C
Yield: 78.7 %

Procedure:
A mixture of 11.0 g (52 mmol) of 2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)-[1,3]-dioxolane, 80 ml of acetone, 40 ml of water, 1.5 ml of conc. hydrochloric acid and 10 g of silica gel was stirred at reflux for 4 hours. After filtration, the solution was diluted with diethyl ether, washed with water, dried (MgSO4) and evaporated in vacuo. Kugelrohr distillation of the residue gave 6.8 g (79% yield) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13]
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.51 mmol) of the compound from Example 41 were introduced into 30 ml of dichloromethane at 0° C., 127 mg (0.51 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 99 mg (48% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:25]=[C:24]([C:26](=[O:28])[CH3:27])[CH:23]=[C:22]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:21]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[Cl-].[NH4+]>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:25]=[C:24]([C:26]([OH:28])([CH2:1][CH3:2])[CH3:27])[CH:23]=[C:22]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:34])[F:35])[N:21]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1
Reactant: CC[Mg]Br
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reaction time: 0.08 h

Procedure:
Ethylmagnesium bromide (0.86 mL, 2.57 mmol, 3M in THF) was dissolved in THF (5 mL). 1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (140 mg, 0.32 mmol) was dissolved in THF (5 mL) and was added slowly to the solution of ethylmagnesium bromide. The mixture was cooled on ice, ammonium chloride (sat, aq, 5 mL) was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as an oil, 63 mg (42%).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[O:7][C@H:4]([O:5][CH3:6])[C@@H:3]1[OH:20].[CH3:21]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[O:7][C@H:4]([O:5][CH3:6])[C@:3]1([CH3:21])[OH:20]
Reactant: CO[C@H]1O[C@H](COC(=O)c2ccccc2C)[C@@H](F)[C@H]1O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COC(=O)c2ccccc2C)[C@@H](F)[C@@]1(C)O
Temperature: -40 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
The product from Step A (1.0 g, 3.5 mmol) and Dess-Martin periodinane (2.5 g) in dichloromethane (20 mL) were stirred overnight at room temperature and was then concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL) and filtered. The filtrate was washed with a solution of Na2S2O3.5H2O (12.5 g) in saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous THF (50 mL). TiCl4 (3 mL) and methyl magnesium bromide in ethyl ether (3 M, 10 mL) were added at −78° C. and the mixture was stirred at −50 to −30° C. for 2 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL) and filtered through Celite. The filtrate was extracted with toluene (100 mL) and evaporated. The residue was chromatographed on silica gel (EtOAc/hexane: 15/85) to afford the title compound as an oil (150 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(#N)C.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Fc1cccc(CBr)c1F
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: N#CCc1cccc(F)c1F
Yield: 100.1 %

Procedure:
2,3-Difluorobenzyl bromide (5 g, 24.2 mmol) in acetonitrile (20 mL) was treated with 18-crown-6 (638 mg, 2.4 mmol) and potassium cyanide (5 g, 77 mmol). The reaction was heated at reflux for 5.5 hours. The reaction was diluted with diethyl ether (100 mL). The resulting organic solution was washed with 1 N NaOH (3×25 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford 3.71 g of crude 2,3-difluorobenzyl cyanide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([Cl:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC#N
Product: O=S(=O)(Cl)N1CCN(Cc2ccccc2)CC1
Yield: 88.8 %

Procedure:
A solution of 1-benzylpiperazine (20.0 g, 0.114 mol) in acetonitrile (45 ml) was added to a solution of sulphuryl chloride (28 ml, 0.346 mol) in acetonitrile (50 ml) and the mixture heated under reflux for 17 hours, then cooled. The solvent was removed by evaporation under vacuum, then the residue triturated with either (20×50 ml) to yield the title compound (27.8 g, 89%), which was used without further purification.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21]>>[CH3:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[O:21][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C[C@@H]1CCC[C@H]1O
Product: C[C@@H]1CCC[C@H]1Oc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 111c from 2,6 dinitrobenzonitrile and trans-2-methylcyclopentanol in 65% as a yellow solid. MS 247 (MH+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][C@@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:14]=2)[O:6][C:5]1=[O:41])([CH3:3])[CH3:2].[NH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(O)(=O)C>[O:48]1[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][NH:42][C:5](=[O:41])[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][C@H:7]([OH:6])[C@@H:9]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:10][C@@H:11]([CH:30]([CH3:31])[CH3:32])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:14]=2)[CH2:46][CH2:47]1
Reactant: NCCN1CCOCC1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCO
Solvent: CC(=O)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Temperature: 45 °C
Reaction time: 6 h

Procedure:
A mixture of 84 mg of 3(S)-isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one, 0.6 ml of 4-(2-aminoethyl)-morpholine and 0.025 ml of glacial acetic acid is stirred for 16 hours at room temperature and for 6 hours at 45° C. and is then partitioned between diethyl ether (2×) and saturated NaHCO3 solution (1×) and water (2×). The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (5 g of silica gel, dichloromethane/methanol=98:2), yielding the title compound: Rf (dichloromethane/methanol=95:5)=0.16; HPLC Rt =14.49 minutes; FAB-MS (M+H)+ =710.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:10][N:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:25]1[CH:24]=[C:23]([C@@H:16]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:15]([NH:14][C:11]2[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)=[O:34])[CH:28]=[CH:27][C:26]=1[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=O)O)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 98.7 %

Procedure:
A solution of 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid tert-butyl ester (3.29 g, 6.48 mmol) in methylene chloride (30 mL) was treated with trifluoroacetic acid (60 mL) and stirred at 25° C. for 65 min. The reaction solution was then concentrated in vacuo The resulting oil was diluted with ethyl acetate (500 mL), washed with water (2×250 mL) and a saturated aqueous sodium chloride solution (5×250 mL), dried over sodium sulfate, treated with decolorizing carbon, filtered through a pad of celite, and concentrated in vacuo to afford the 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid (2.89 g, 99%) as a light yellow foam: mp 121–127° C.; (ES)+-HRMS m/e calcd for C20H22ClN3O5S (M+H)+ 452.1042, found 452.1046. This material was used without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.20 g (0.66 mmol) of methyl 5-(3-cyclopentoxy-4-methoxyphenyl)-2,4-E,E-pentadienoate 75 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 52 minutes after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 7.5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be as analytically pure as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2]>C(OCC)(=O)C.ClCCl.[Pd]>[CH2:1]([O:3][C:4](=[O:45])[CH2:5][NH:6][C:7]([C:9]1[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:38]=[CH:39][C:40]([CH2:43][OH:44])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
Ethyl({[5-(benzyloxy)-2-({1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.43 g, 0.71 mmol) was dissolved in a mixed solvent of ethyl acetate (20 mL) and dichloromethane (20 mL), and 10% palladium-activated carbon (0.080 g) was added, followed by stirring at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (0.34 g, 0.66 mmol) as a white solid (yield 93%).