Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>CCO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[O:16]
Reactant: [H][H]
Reactant: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCNC(=O)c1cccc(N)c1

Procedure:
To a solution of N-(2-dimethylaminoethyl)-3-nitrobenzamide (21.0 g, 88.0 mmol) in EtOH (50 mL) was added 10% Pd/C (2.52 g) and the hydrogenated with hydrogen at 35 psi for 3 h. The reaction mixture was filtered through a pad of Celite, the filterate was evaporated to dryness and the solid obtained was recrystallize from EtOH to give 3-amino-N-(2-dimethylaminoethyl)benzamide; 17.19 g (93%); mp 97-100° C.; 1H NMR (CDCl3) δ 2.20 (6H, s, 2×Me), 2.52 (2H, J=5.8 Hz, CH2), 3.51 (2H, q, J=5.4 and 5.8 Hz, CH2), 3.80 (2H, brs, exchangeable, NH2), 6.75-6.80 (1H, m, ArH), 6.82 (1H, brs, exchangeable, NH), 7.10 (H, d, J=7.6 Hz, ArH) 7.12-7.30 (2H, m, ArH) 8.33 (1H, m, ArH), 8.66 (1H, s, ArH). Anal Calcd. for (C11H17N3O): C, 63.74; H, 8.27; N 20.27. Found: C, 63.51, H, 8.45; N 20.12.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:11][OH:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:12][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]=1[O:13][CH3:14])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(COS(C)(=O)=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.43 g (5-tert-butyl-2-methoxy-3-nitro-phenyl)-methanol are dissolved in 30 ml dichloromethane, combined with 2.39 ml of triethylamine and cooled to 0° C. 1.2 g of methanesulphonic acid chloride are added dropwise and the mixture is stirred for 2 hours. Then it is diluted with dichloromethane and washed 3 times with water and once with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCOCC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with morpholine and pyridine in chloroform. [α]D20=+43.1° (c=1.05, CHCl3), ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=2[CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]([C:20]#[N:21])=[C:16](SC)[N:17]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[OH:35][CH2:34][CH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:16]2[N:17]=[C:12]([CH2:11][C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:14](=[O:22])[C:15]=2[C:20]#[N:21])[CH2:28][CH2:29]1
Reactant: COc1ccc(-c2ccccc2Cc2nc(SC)c(C#N)c(=O)[nH]2)cn1
Reactant: OCCC1CCNCC1
Product: COc1ccc(-c2ccccc2Cc2nc(N3CCC(CCO)CC3)c(C#N)c(=O)[nH]2)cn1

Procedure:
In analogy to the preparation of Example 1, 80 mg (0.22 mmol) of 2-[2-(6-methoxypyridin-3-yl)-benzyl]-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 85 mg (0.65 mmol) of 2-(4-piperidinyl)ethan-1-ol to give 62 mg (63% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>CN(C)C=O.O>[CH3:20][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:10])=[CH:12]1
Reactant: CI
Reactant: O=S(c1ccccc1)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(S(=O)c2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride in mineral oil (60% suspension, 0.036 g, 0.90 mmol) was suspended in dry dimethylformamide (10 ml) and a solution of 3-phenylsulfinylindole (0.200 g, 0.82 mmol) in dry dimethylformamide (10 ml) was added dropwise thereto with stirring. After 0.5 hours at room temperature, methyl iodide (0.057 ml) was added and fifteen minutes thereafter the mixture was diluted with water. The product was extracted into benzene, the extract dried and evaporated in vacuo. Crystallization of the residue from ethyl acetate-ether gave the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1C[O:19]CC1.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]([OH:19])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC2CC1CN2Cc1ccccc1
Reactant: C1CCOC1
Agent: B
Agent: O=C([O-])[O-]
Agent: OO
Solvent: ClCCl
Solvent: O
Product: OC1CC2CC1N(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a round bottom flask was added 2-benzyl-2-azabicyclo[2.2.1]hept-5-ene (1 g, 5.40 mmol) and THF (7 mL). The reaction was cooled to 0° C. and 1N BH3.THF (10.80 mL, 10.80 mmol) was slowly added to the reaction. The reaction was stirred at 0° C. for 1 hr and then water (0.5 ml) was added to the reaction dropwise to quench the excess BH3. 1N NaOH (5.94 mL, 5.94 mmol) and 30% H2O2 (0.182 mL, 5.94 mmol) were added to the reaction and the reaction was stirred at 40° C. for 1 hr. The reaction was cooled to rt and K2CO3 (1 g) was added. The reaction was diluted with CH2Cl2 (50 ml) and washed with water (2×20 ml) and saturated aqueous NaCl (30 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC. The major peak was collected and fractions were concentrated to give 2-benzyl-2-azabicyclo[2.2.1]heptan-6-ol (850 mg, 4.18 mmol, 77% yield). Anal. Calcd. for C13H17NO m/z 203.3, found: 204.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.48-7.32 (m, 5H), 4.47 (d, J=6.60 Hz, 1H), 4.29 (br. s., 1H), 4.23-4.05 (m, 2H), 3.78 (s, 1H), 3.29 (dd, J=11.00, 4.40 Hz, 1H), 2.81-2.72 (m, 1H), 2.68 (br. s., 1H), 2.09 (d, J=11.55 Hz, 1H), 2.04-1.95 (m, 1H), 1.77 (d, J=12.10 Hz, 1H), 1.60-1.50 (m, 1H); 13C NMR (126 MHz, CDCl3) δ ppm 130.61, 130.04, 129.42, 68.31, 67.72, 59.17, 58.03, 37.98, 35.49, 31.24.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][C:4]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([N:22]3[C:34](=[O:35])[C:33]4[S:32][C:31]5[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=5[C:25]=4[CH:24]=[N:23]3)[C:17]=2[CH:36]=[O:37])=[CH:3]1.[BH4-].[Na+]>CO>[OH:37][CH2:36][C:17]1[C:18]([N:22]2[C:34](=[O:35])[C:33]3[S:32][C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[C:25]=3[CH:24]=[N:23]2)=[N:19][CH:20]=[CH:21][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2CO)cc(Nc2ccncn2)c1=O
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
At room temperature, to a solution of 182a (140 mg, 0.27 mmol) in methanol (5 mL) was added sodium borohydride (31 mg, 0.82 mmol). The reaction mixture was stirred for 20 minutes and quenched with water (1 mL). It was then concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 182 as a white solid (60 mg, 43%). MS-ESI: [M+H]+ 514.2. 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J=2.5 Hz, 1H), 8.82 (s, 1H), 8.70 (d, J=5.5 Hz, 1H), 8.36 (d, J=6.5 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.55 (d, J=5.0 Hz, 1H), 6.80 (d, J=9.5 Hz, 1H), 4.44-4.42 (m, 3H), 3.75 (s, 3H), 2.99-2.98 (m, 2H), 2.88-2.87 (m, 2H), 2.03-1.98 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[N:11](COCC[Si](C)(C)C)[CH:10]=2)=[O:8])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl.O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:3][C@H:4]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=5)[N:20]([CH3:28])[N:19]=4)[N:16]=3)[NH:11][CH:10]=2)=[O:8])[CH2:5]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4C[C@H](O)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
In a flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-hydroxy-cyclobutyl)-amide (100 mg, 0.20 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (0.61 mL, 7.92 mmol) was added and the orange solution was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue (light orange foam) was suspended in dichloromethane (1.0 mL) and ethylenediamine (0.80 ml, 11.8 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate. The suspension was filtered and washed with water (hot) and ethyl acetate. The resulting off-white powder was dried under high vacuum to provide 55 mg (66%; purity=90%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-hydroxycyclobutyl)-amide. LC/MS: [M−H]−=379. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.31-12.64 (br. s., 1H), 9.10 (s, 1H), 8.52 (dd, J=9.0, 5.2 Hz, 1H), 8.43 (s, 1H), 8.36 (d, J=7.1 Hz, 1H), 7.72 (dd, J=9.7, 2.1 Hz, 1H), 7.20 (td, J=9.1, 2.3 Hz, 1H), 5.19-5.26 (m, 1H), 4.52-4.61 (m, 1H), 4.44-4.61 (m, 1H), 4.16 (s, 3H), 2.25-2.40 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.C(OCC)(=O)C>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cn1
Yield: 17.3 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride (60% in oil, 200 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as an oil (yield 59 mg, 17%).
Reaction SMILES: [C:1]1([O:11][CH:12](Br)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1CCCCC1>[C:1]1([O:11][CH:12]([N:29]2[CH2:28][CH2:27][CH:26]([N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]2)[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Oc1cccc2ccccc12
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Solvent: C1CCCCC1
Product: CCC(=O)N(c1ccccc1)C1CCN(C(C)Oc2cccc3ccccc23)CC1

Procedure:
Using the procedure of Example I step B and starting from (α-naphtoxyethyl) bromide and 4(N-phenyl N-propionylamino) piperidine, N(α-naphtoxyethyl) 4-(N'-phenyl-N'-propionylamino) piperidine is obtained melting at 110°-112° (cyclohexane).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CN(C)c1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
Analogously to Example 12, 13.9 g (110 mmol) of 2-fluorobenzylamine, 21.3 g (110 mmol) of 4,6-dichloro-2-(N,N-dimethylamino)-pyrimidine and 11.5 g (114 mmol) of triethylamine are dissolved in 300 ml of absolute ethanol and the mixture is heated under reflux for 48 hours. After the ethanol has been removed by distillation, water is added to the residue, the product is filtered off with suction and recrystallisation from cyclohexane yields 4-chloro-2-(N,N-dimethylamino)-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 71°-73°.
Reaction SMILES: CN[C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.Cl[Si](C)(C)C.[C:27]1(=[O:32])CCC=C1>CCOCC.[Cu]I>[CH2:16]([C@H:11]1[CH2:3][CH2:4][C:27](=[O:32])[CH2:12]1)[CH2:15][CH2:14][CH3:13]
Reactant: O=C1C=CCC1
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[C@H]1CCC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (360.0 mg, 1.65 mmol) was dissolved in ether (12 mL) and n-butyl lithium (2.5M in hexanes, 0.66 mL, 1.65 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (262 mg, 1.38 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.55 mL, 1.38 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 5 min, chlorotrimethylsilane (0.437 mL, 3.44 mmol) was added and stirred for 15 min. 2-Cyclopentenone (112.8 mg, 1.38 mmol) was added slowly at -78° C. to the reaction mixture, which was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (5:1=pentane/ether) to afford (S)-3-n-butylcyclopentanone (98.7 mg, 51% chemical yield, 44% ee, [α]D =-54.4 (c=3.00, benzene)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][CH2:27][C:17]1([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:29])[CH2:15][CH2:16]1)=[O:6]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: COc1ccc(Cl)c(C(=O)O)c1
Product: COc1ccc(Cl)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-chloro-5-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=413.1, tR (minutes, Method D)=0.72
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][F:33]>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][F:33])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: FCCCCCCCBr
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCCCF)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV) a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-7-fluoroheptane (Step II) to give N-[4-[4-[ethyl(7-fluoroheptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, a compound of Formula I'. A mixture of this compound and 0.5 equivalents of fumaric acid was crystallized from acetone to give the titled product, mp 137°-138° C. Anal. calc'd for C22H37N2O5S: C, 57.36; H, 8.10; N, 6.08; S, 6.96. Found: C, 57.34; H, 8.08; N, 6.03; S, 6.95.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: CN(C)CCCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN1CCNCC1
Temperature: 25 °C
Reaction time: 38 h
Yield: 97.3 %

Procedure:
A mixture of 4-benzyloxycarbonyl-3-dimethylaminopropylpiperazine (2.21 g, 7.2 mmol), 5% Pd/C (0.36 g) in methanol (20 ml) was stirred under hydrogen atmosphere at room temperature for 38 h. After removal of catalyst by Celite filtration, the filtrate was concentrated to afford 1.20 g (97.6%) of orange color viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a pre-cooled suspension of 2-bromo-5-fluorophenol (5 g, 26.18 mmol) and potassium carbonate (10.84 g, 78.54 mmol) in DMF (15 mL) at 0-5° C., was added methyl iodide (4.75 mL, 39.27 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated brine solution (20 mL) and dried over Na2SO4, filtered and concentrated in vacuo to afford 1-bromo-4-fluoro-2-methoxybenzene as a colourless liquid in 93% yield, 5.00 g.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1)([CH3:50])([CH3:49])[CH3:48].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C)C=O>[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:58][CH:57]=1)([CH3:49])([CH3:50])[CH3:48]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (210 mg), 4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride (144 mg), diethylphosphorocyanidate (75 mg) and triethylamine (93 mg) in dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:2) to yield the title compound (328 mg, yield 99%) as a colorless wax-like substance.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8].[NH2:12][C:13]1[S:14][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[N:16][N:17]=1.O>CN(C)C(=O)C>[C:20]1([C:18]([C:15]2[S:14][C:13]([NH:12][C:7](=[O:8])[C:6]([OH:5])([CH3:11])[CH3:10])=[N:17][N:16]=2)=[O:19])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1nnc(C(=O)c2ccccc2)s1
Reactant: CC(C)(O)C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(O)C(=O)Nc1nnc(C(=O)c2ccccc2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (60 μl, 0.82 mmol) is added to 2-hydroxyisobutyric acid (82.9 mg, 0.796 mmol) in 5.0 ml of N,N-dimethylacetamide at -20°/-15° C. and the mixture is stirred at -15°/-10° C. for one hour. After adding 2-amino-5-(phenylcarbonyl)-1,3,4-thiadiazole (97.5 mg, 0.475 mmol) and equilibrating the reaction mixture to room temperature, it is stirred overnight. The reaction mixture is poured into 75 ml of water and subjected to extraction with 3×25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33.% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])(C)(C)C.CN(OC)[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[C:7]3[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:35])=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(C(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.21 gm (1.05 mMol) potassium hydride in 5.0 mL tetrahydrofuran at 0° C. were added a solution of 0.3 gm (1.0 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole in 5.0 mL tetrahydrofuran and the solution stirred for about 30 minutes. The resulting mixture was cooled to about -78° C. and to it were added 1.47 mL (2.3 mMol) t-butyllithium, which had been precooked to -78° C., via cannula. After about 15 minutes, a solution of 1.0 gm (5.0 mMol) N-methyl-N-methoxy-4-chlorobenzamide (Preparation VII) in 3.0 mL tetrahydrofuran were added. The reaction mixture was allowed to gradually warm to ambient and was then quenched with 2N sodium hydroxide. The mixture extracted well with diethyl ether and the ether extracts were then washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by radial chromatography (2 mm silica), eluting with 95:5 ethyl acetate:methanol, to give the title compound as a light yellow solid.