Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(N)=CC=CN=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]2)=[CH:12][CH:11]=1.[CH2:38]([OH:40])[CH3:39]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][NH:35][C:36](=[S:37])[O:40][CH2:38][CH3:39])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: CCO
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Agent: Nc1cccnc1Cl
Product: CCOC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 1.3 parts of 2-chloro-3-pyridinamine, 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated. Water and ammonia were added to the residue and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.4 parts of ethyl [2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamothioate; mp. 148.6° C. (compound 35).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.P(OCC)(OCC)[O:30]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC)(C)(C)C.Cl>C1COCC1>[CH:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[CH:25]([OH:30])[C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:19][C:18]3=[O:28])[CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Buspirone (8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4.5)-decane-7,9-dione) (246.5 g, 639.6 mmol) was charged to a 12 L flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (4.383 kg, 60.8 mol, 4.930 L, 20 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (371.9 g, 2.238 mol, 383.8 mL, 3.5 eq) was added and the mixture was cooled to −68 to −75° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (600.4 g, 664.1 mmol, 664.1 mL, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of buspirone. Additional buspirone in THF (10-20 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 0.5% to 5% excess of buspirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (384.8 g, 4.365 mol, 520.0 mL) was added followed by 1M hydrochloric acid (1350.8 g, 1.328 mmol, 1328 mL) and the solution was warmed to ambient temperature. The pH was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4. The phases were separated and the organic phase was washed twice with brine (542.3 g, 493 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to crystallize the reaction product. There is an option to seed with 0.01 to 5% buspirone at approximately 54 to 56° C. The crystalline slurry was then filtered and the wet cake was washed with isopropyl alcohol and dried to provide 6-hydroxybuspirone (220.0 g, 82%), mp 109.5° C.
Reaction SMILES: C1(C2(C(O)=O)CCCC2)C=CC=CC=1.C[CH:16](C)[CH:17]([C:40]1C=C[CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:37][C:36]([F:38])([F:39])[C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH2:27][C@H:28]2[C@@H:21]([NH:20][C:18]([CH:17]3[CH2:16][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:19])[CH2:22][CH2:23][C@H:24]2[CH2:25]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: O=C(O)C1(c2ccccc2)CCCC1
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.74 (d, J=6.1, 1H), 7.71 (s, 1H), 7.62 (d, J=7.7, 1H), 7.57 (d, J=9.2, 1H), 7.47 (t, J=7.7, 1H), 4.48-4.41 (m, 1H), 3.53 (d, J=13.2, 1H), 3.47 (d, J=13.2, 1H), 2.84 (ddd, J=2.8, 7.9, 10.3, 1H), 2.75 (dd, J=2.8, 9.5, 1H), 2.51-2.43 (m, 1H), 2.37 (dd, J=2.8, 9.1, 1H), 2.34-2.29 (m, 1H), 2.27-2.19 (m, 2H), 1.94-1.83 (m, 2H), 1.80 (d, J=12.9, 1H), 1.73-1.60 (m, 6H), 1.57-1.51 (m, 1H), 1.35-1.27 (m, 1H), 1.22-1.10 (m, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=[N:21][OH:22])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)N1C2CCCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)N1C2CCCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no: 56258-85-6) (5.0 g, 28 mmol) in ethanol (125 mL) and pyridine (3.3 mL, 41 mmol) with hydroxylamine hydrochloride (2.03 g, 29 mmol) was refluxed for 6 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (4.43 g, 82%); MS: m/e=197.1 (M+H−).
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:22][C:23]([CH2:26][NH:27][C:2]2[N:3]([C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=3[N:18]=2)[C@@H:4]2[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]2)=[CH:24][CH:25]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1nc(NCc1ccc(-c3ccccc3)cc1)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A mixture of 8-bromo-2′-deoxyadenosine (0.07 g), biphenyl-4-ylmethylamine (0.12 g) and N,N-diisopropyl-ethylamine (0.15 mL) in 1-propanol (2.1 mL) was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=12/1) to give the title compound (0.05 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:15])[N:10]1[CH2:14][CH2:13][S:12][CH2:11]1)(C)(C)C.[ClH:17].O1CCOCC1>>[ClH:17].[NH2:7][CH2:8][C:9]([N:10]1[CH2:14][CH2:13][S:12][CH2:11]1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCSC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Oxo-2-thiazolidin-3-yl-ethyl)-carbamic acid tert-butyl ester (5.41 g, 22 mmol) was dissolved in 4M HCl-dioxane (80 mL) at 0° C. The resulting solution was stirred at 25° C. for 2 hours, concentrated and the residue triturated with ether. Yield, 3.9 g, 97 %.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[N:6]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:17])[CH3:18])=[C:9]([Cl:8])[CH:10]=2)[S:4][N:3]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1Cl
Reactant: Clc1nc(Br)ns1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Temperature: 80 °C
Yield: 96.4 %

Procedure:
To a solution of 3-bromo-5-chloro-1,2,4-thiadiazole (558 mg), {3-chloro-4-[(1-methylethyl)oxy]phenyl}boronic acid (300 mg) and tripotassium phosphate (148 mg) in N,N-dimethylformamide (DMF) (3 mL) and water (0.600 mL) under nitrogen was added PdCl2(dppf)-CH2Cl2 adduct (3.427 g). The reaction vessel was sealed and heated under microwave at 80° C. for 1 h. After cooling the reaction, the mixture was filtered and the filtrate was diluted with ethyl acetate (50 mL), washed with brine (2*10 mL), dried over sodium sulphate, concentrated and purified by column chromatography to afford 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (450 mg) as a clear oil. MS (ES): C11H10BrClN2OS requires 332. found 333.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(O)C>[Cl:1][C:2]1[C:3]([CH:12]([CH2:15][CH3:16])[CH2:13][NH:14][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(CN)c1ncc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCC(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl

Procedure:
100 mg of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1-butanamine (0.0004 mol), 58 μL of 2-(trifluoromethyl)benzoic acid(0.0004 mol), 0.109 g of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.0004 mol) are stirred in 2 mL of ethanol at room temperature overnight.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:27])[CH3:2].[O:30]1[CH2:35][CH2:34][N:33]([C:36]([CH2:38][CH2:39][C:40]#[CH:41])=[O:37])[CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:41]#[C:40][CH2:39][CH2:38][C:36]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)=[O:37])[CH:13]=2)[C:8]([OH:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:27])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCCC(=O)N1CCOCC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(C#CCCC(=O)N1CCOCC1)cc2C(F)(F)F
Yield: 106 %

Procedure:
The title compound (65.2 mg, 88%) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(phenyl)oxindole (57.2 mg) and 4-morpholinocarbonyl-1-butyne (31.1 mg) by the procedure similar to that described in Reference Example 21. The compound obtained was further purified by reverse phase HPLC with water-acetonitrile-trifluoroacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])([O-])=O.O.O.Cl[Sn]Cl.N.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C=Cc1cccc(N)c1
Yield: 99.5 %

Procedure:
Crude allyl 3-nitrocinnamate (3 g, 12.9 mM) was dissolved in ethyl acetate (10 ml) and added slowly to a stirred suspension of SnCl2.2H2O(14.52 g, 64 mM) in ethyl acetate (20 ml). The mixture was refluxed under argon for 3 hours, cooled, and poured into a mixture of ammonia (sg 880, 15 ml) and water (5 ml). Ethyl acetate (50 ml) was added, and the organic layer separated by decantation. Two further extractions with ethyl acetate (each 50 ml) were made similarly. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to give title compound (2.6 g).
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH3:20])[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>CO>[CH3:20][CH:11]([CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:10][OH:9]
Reactant: CC(COC(=O)c1ccccc1)COC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CO)COC1CCCCO1
Yield: 88.4 %

Procedure:
1-Benzoyloxy-2-methyl-3-tetrahydropyranyloxypropane (460 mg; 1.65 mmol) was dissolved in methanol (10 ml), and 1M sodium hydroxide solution (3 ml) and water (10 ml) were added thereto, and the resultant mixture was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous magnesium sulfte. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography using a mixture of ethyl acetate and benzene (1:4) to give 2-methyl-3-tetrahydropyranyloxy-1-propanol (254 mg; yield, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([O:38][CH3:37])[CH3:49])=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 691.3 [(M+H)+]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-:3])=[O:2].Cl[CH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:31])=[CH:40][CH:41]=1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=C(NCc1ccccn1)c1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccn1)c1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
8-(2-nitrobenzenesulfonyl)amino-5,6,7,8-tetrahydroquinoline (402 mg, 1.20 mmol), 4-Chloromethyl-N-pyridin-2-ylmethyl-benzamide (314 mg, 1.20 mmol), and K2CO3 (498 mg, 3.60 mmol) were heated to reflux in CH3CN (4 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, then brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, using 50% ethyl acetate in CH2Cl2, afforded the title compound (603 mg, 90%) as white foam. 1H NMR (CDCl3) δ 1.56-1.61 (m, 1H), 1.74-2.05 (m, 2H), 2.32-2.36 (m, 1H), 2.58-2.64 (m, 2H), 3.95 (d, 1H, J=16.2 Hz), 4.74 (d, 2H, J=4.5 Hz), 4.85 (d, 1H, J=15.9 Hz), 5.30 (dd, 1H, J=11.1, 17.4 Hz), 7.05 (dd, 1H, J=4.5, 7.5 Hz), 7.22-7.29 (m, 2H), 7.34 (dd, 2H, J=7.5, 7.8 Hz), 7.48-7.73 (m, 8H), 8.12-8.15 (m, 1H), 8.20-8.24 (m, 1H), 8.45-8.59 (m, 1H); ES-MS m/z 558.2 (M+H).
Reaction SMILES: BrC1C=C2C(C3C=CC([OH:17])=CC=3)=CNC2=NC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Br-].[Na+]>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([OH:17])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
2.82 g (9.75 mmol) of 4-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-phenol and 3.10 g of para-toluenesulfonyl chloride were dispersed in 400 ml of toluene at 45° C. 45 ml of 50% aqueous solution of KOH and 1.5 ml of 40% aqueous solution of tetra-n-butylammonium hydroxide were added and the resulting mixture stirred vigorously at ambient temperature for 6 h. The resulting mixture was diluted with 100 ml of a saturated aqueous solution of sodium bromide, the phases separated and the aqueous layer extracted three times with toluene. The combined organic phases were washed with a 2 M aqueous solution of sodium hydroxide, dried over sodium sulfate and evaporated. The crude was crystallized from ethanol containing 10% v/v of toluene to afford 3.22 g (5.29 mmol, 55% yield) of toluene-4-sulfonic acid 4-[(5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-phenyl ester as ivory crystalline needles.
Reaction SMILES: [C:1]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC2C=CC(OC)=CC=2)=[O:26])[CH:14]=1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(C1C2C(=CC=CC=2)N(CCCC(OCC2C=CC(OC)=CC=2)=O)C=1)(=O)/C=C/CCCCCC>>[C:1]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:14]=1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Agent: CCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12
Product: CCCCCCCC/C=C/C(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 45 was repeated except that (E)-4-methoxybenzyl 4-[3-(2-undecenoyl)-1-indolyl]butyrate obtained in Ex. 48 was used in place of (E)-4-methoxybenzyl 4-[3-(2-none-noyl)-1-indolyl]butyrate to give (E)-4-[3-(2-undecenoyl)-1-indolyl]butyric acid.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].Cl.C(=O)([O-])[O-].CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH:39][CH2:28][C@H:26]([OH:27])[CH2:25][O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:31][CH3:32])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[O:16][N:15]=2)=[CH:18][C:19]=1[CH2:29][CH3:30])[CH3:35]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CNC[C@H](O)COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Yield: 9.7 %

Procedure:
A solution of (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.15 mmol), glycine ethylester hydrochloride (320 mg, 2.30 mmol), of which the hydrochloride was removed by filtration over a carbonate loaded silica resin prior to use, and DIPEA (0.2 mL) in methanol (3 mL) is stirred at 60° C. for 3 days. The mixture is diluted with DCM and washed with sat. aq. NaHCO3 solution. The aq. phase is extracted once with DCM. The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. TLC using DCM:methanol 9:1 to give (S)-2-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-2-hydroxypropyl)amino)acetic acid ethyl ester (60 mg) as a white solid; LC-MS: tR=1.03 min, [M+H]+=537.29.
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])(C)C.N1C=CN=C1>CN(C=O)C>[CH2:30]1[CH2:1][O:2][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:31][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:29]1
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of methyl 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-hydroxycyclopentyl]acetate (61) in DMF (80 ml) were added t-butyldimethylsilyl chloride (2.11 g) and imidazol (0.95 g), and the resultant mixture was stirred. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (62).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][O:13][CH2:12]2.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][O:13][CH2:12]3)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cc(N2C3CCC2COC3)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
In a 250 mL round-bottomed flask was placed 2,4,6-trichloropyrimidine (8, 0.575 mL, 5 mmol) in EtOH (20 mL) to give a colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 748 mg, 5.00 mmol) was added and the solution was cooled to 0° C. Triethylamine (2.091 mL, 15 mmol) was added slowly and the mixture was allowed to slowly warm to room temperature. The mixture was stirred at room temperature for one hour and was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (5-20%) to give the title compound (980 mg, 75%) as a white solid.