Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:30][O:31][CH2:32][C@H:33]([CH3:53])[O:34][C:35]1[CH:36]=[C:37]([OH:52])[CH:38]=[C:39]([C:41]2[NH:42][C:43]([C:46]3[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=3)=[CH:44][CH:45]=2)[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:52][C:37]3[CH:38]=[C:39]([C:41]4[NH:42][C:43]([C:46]5[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=5)=[CH:44][CH:45]=4)[CH:40]=[C:35]([O:34][C@@H:33]([CH3:53])[CH2:32][O:31][CH3:30])[CH:36]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (288 mg, 0.67 mmol) synthesized in Example (120b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (160 mg, yield 33%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:25])=[N+:7]2[O-].C(OC(=O)C)(=[O:28])C.CO>C(O)(=O)C>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:25][OH:28])=[N:7]2
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1Br
Temperature: 110 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A solution of S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline 1-oxide (497 mg, 1.21 mmol) in acetic acid (12 mL) was heated at 80° C. for 15 minutes. To the solution was added acetic anhydride (1.37 mL, 14.5 mmol) and the resulting solution was heated at 110° C. for 2 hours. The reaction mixture was cooled to 50° C. and methanol (6 mL) was added and stirred for 1 hour. The reaction was cooled to room temperature and concentrated. The resultant oil was taken up in tetrahydrofuran (20 mL) to which was added 6 M potassium hydroxide (20 mL) and stirred for 1 hour. The product was extracted with ethyl acetate and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (366 mg, 74%). LCMS-ESI+ (m/z):
Reaction SMILES: C1(B(O)O)C=CC=CC=1.C(C1C=CC(B(O)O)=CC=1)CCC.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[CH:36][O:35][C:34]=2[C:38]([NH:40][NH2:41])=[O:39])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].C([O:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[N+:55]([O-:57])=[O:56])(=O)C.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[OH:45][C:46]1[CH:54]=[CH:53][C:49]([C:50]([NH:41][NH:40][C:38]([C:34]2[O:35][CH:36]=[CH:37][C:33]=2[C:30]2[CH:29]=[CH:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:32][CH:31]=2)=[O:39])=[O:51])=[CH:48][C:47]=1[N+:55]([O-:57])=[O:56]
Reactant: CCCCc1ccc(-c2ccoc2C(=O)NN)cc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCCCc1ccc(B(O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: OB(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCc1ccc(-c2ccoc2C(=O)NNC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1
Reaction time: 2 h

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 14 except that the phenylboronic acid used in Reference Example 14 was replaced with 4-butylphenylboronic acid, thereby giving 3-(4-butylphenyl)-2-furancarboxylic acid hydrazide. This 3-(4-butylphenyl)-2-furancarboxylic acid hydrazide (1.62 g), 4-acetoxy-3-nitrobenzoic acid (compound of Reference Example 80, 1.66 g), WSC (1.50 g) and DMF (25 ml) were stirred at 25° C. for 2 hours. The reaction solution was diluted with chloroform and successively washed with water, 20% citric acid solution, aqueous saturated sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. After dissolving the residue in ethanol (15 ml), 2 M aqueous sodium hydroxide solution (16 ml) was added at 25° C. and stirred for 2 hours. The reaction solution was neutralized with hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile, thereby giving 1.80 g of the desired compound.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24]NC.Cl[C:28]1C=CC=CC=1Cl>>[IH:1].[C:2]1([CH:8]([N:9]=[C:10]2[N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:13]2[CH3:28])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: Clc1ccccc1Cl
Reactant: CNCCCNC
Agent: I
Product: CN1CCCN(C)C1=NC(c1ccccc1)c1ccccc1
Yield: 59.8 %

Procedure:
To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 200 milliliters of o-dichlorobenzene was added 10.22 grams (0.10 mole) of N,N'-dimethyl-1,3-propanediamine and the resulting mixture heated under reflux for 21 hours. The reaction mixture was cooled, the solvent decanted therefrom and isopropanol added to the gummy residue to obtain 24.35 grams (59.8 percent yield) of 2-diphenylmethylimino-1,2,3,4,5,6-hexahydro-1,3-dimethylpyrimidine hydroiodide product of m.p. 215°-219° C. After two recrystallizations from methanol-isopropanol, a purified product, m.p. 221° C., was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC(CCCO)COc1ccc(F)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
A solution of p-toluenesulfonyl chloride (42.0 g., 0.22 mole) in pyridine (100 ml.) is cooled in an ice bath while 4-acetoxy-5-(4-fluorophenoxy)-1-pentanol (49.7 g., 0.193 mole) is added dropwise with stirring during 40 minutes. The ice bath is replaced by a cool (20°) water bath and stirring is continued for 2 hours. The mixture is then poured into 500 ml. of water. The oily product is taken up in ether, washed with 2N hydrochloric acid and water and dried over sodium sulfate. The solvent is distilled in vacuo to leave 73.5 g. (93%) of the crude title compound as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.CCO.Cl.C([Cl:36])(=O)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([Cl:27])[CH:24]=1)[O:20][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1.[ClH:36]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2cc(Cl)cc(Cl)c2)c2ccccc2)C1
Agent: Cl
Solvent: CCO
Product: Clc1cc(Cl)cc(O[C@H](c2ccccc2)[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester (14.0 g, 33.1 mmol) was dissolved in EtOH (100 mL, 2 mol). Into the mixture was added an HCl solution prepared by the slow addition of acetyl chloride (23.6 mL, 331 mmol) into EtOH (50 mL, 860 mmol) at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation, EtOAc (200 mL) was added, followed by removal of most of the solvent. EtOAc (50 mL) was added, the solution was heated to 75° C. for 15 minutes, cooled to room temperature, filtered and dried to yield (R)-3-[(S)-(3,5-dichlorophenoxy)phenylmethyl]pyrrolidine as an HCl salt (10.5 g, >99% purity).
Reaction SMILES: [CH2:1](N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[O:13]1C[CH2:16][CH2:15][CH2:14]1>ClCCl>[CH3:1][O:11][C:8]1[CH:16]=[CH:15][C:14]([OH:13])=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)Cl
Reactant: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(O)cc1
Temperature: 25 °C

Procedure:
12.08 g of 4-arm PEG 15 k (Mn=14861 g/mol, 3.3 meq OH) were dissolved in 150 ml of dry tetrahydrofuran under an Ar atmosphere. The solution was dried by refluxing the solvent over molecular sieves until the water content had fallen below 100 ppm, after which it was allowed to cool down to room temperature. 0.78 g of triethylamine (7.7 mmol) were added and a solution of 0.69 g of acryloylchloride (7.7 mmol) in 20 ml of dry dichloromethane was added drop wise at such a rate that the temperature of the reaction mixture remained below 30° C. The resulting suspension was filtered through ca. 1 cm of Celite 545, yielding a pale yellow, clear solution to which 44 mg of MEHQ were added. The solvent was removed by rotary evaporation, the resulting solid was redissolved in 150 ml of water and NaHCO3 was added until pH 8. The aqueous solution was washed twice with 40 ml of diethyl ether, 10 g of NaCl were added and the product was extracted with four 50 ml portions of dichloromethane. The combined organic layers were dried with Na2SO4 and filtered. To the resulting pale yellow solution 30 mg of MEHQ were added and it was concentrated to ca. 35 ml by rotary evaporation. Precipitation in 0.8 l of cold diethyl ether and subsequent filtration and drying at 60° C. in a vacuum oven yielded 11.5 g (94%) of a white powder. The structure of the product was confirmed by 1H NMR, which showed a degree of functionalization of ca. 97%.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5](Cl)[N:4]=1.[OH-].[Na+].[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[C:5]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1
Reactant: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nc(OCc2ccccc2)c2ncn(CC(=O)O)c2n1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Sodium (2.0 g; 87.0 mmol) was dissolved in benzyl alcohol (20 ml) and heated to 130° C. for 2 h. After cooling to 0° C., a solution of 2-amino-6-chloro-9-carboxymethylpurine (4.05 g; 18.0 mmol) in DMF (85 ml) was slowly added, and the resulting suspension stirred overnight at 20° C. Sodium hydroxide solution (1N, 100 ml) was added and the clear solution was washed with ethyl acetate (3×100 ml). The water phase then was acidified to a pH of 3 with 4 N hydrochloric acid. The precipitate was taken up in ethyl acetate (200 ml), and the water phase was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with saturated sodium chloride solution (2×75 ml), dried with anhydrous sodium sulfate, and taken to dryness by evaporation, in vacuo. The residue was recrystallized from ethanol (300 ml). Yield after drying, in vacou, over sicapent: 2.76 g (52%). M.p. 159-65° C. Anal. (calc., found) C, (56.18; 55.97), H, (4.38; 4.32), N, (23.4; 23.10). 1H-NMR (DMSO-d6): 4.82 ppm.(s,2H); 5.51 (s,2H); 6.45 (s,2H); 7.45 (m,5H); 7.82 (s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.[NH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:48])[C@@H:36]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:47])=[N:43][N+:44]([O-:46])=[O:45])[NH2:37])=[CH:29][CH:28]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[NH2:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][NH:34][C:35](=[O:48])[C@@H:36]([CH2:38][CH2:39][CH2:40][NH:41][C:42]([NH2:47])=[N:43][N+:44]([O-:46])=[O:45])[NH:37][C:10](=[O:12])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:32]=1)=[O:24]
Reactant: COc1ccc(C(C(=O)O)c2ccc(OC)cc2)cc1
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc(C(C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccc(OC)cc2)cc1
Yield: 48 %

Procedure:
Prepared analogously to Example 14c) from bis-(4-methoxyphenyl)-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamidehydrochloride and TBTU in a yield of 48% of theory. Colourless crystals, Mp. 149-151° C. (Acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][OH:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cl
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Yield: 91 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, 5.00 g), hydroxylamine hydrochloride (1.30 g) and concentrated hydrochloric acid (1 mL, 1.05 g) in MeOH (methanol) (37.5 mL) was stirred at 70° C. for 4 h. After cooling, the mixture was freed from all volatiles by evaporation and partitioned between MTBE and water. The organic layer was separated and dried. Chromatography over silica gel yielded the title compound (4.70 g, 91%).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[N:7]=1)(=O)=O.[CH2:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C.N1CCCC[CH2:31]1.C(OCC)(=O)C>CN(C=O)C.O>[N:25]1([CH2:23][C:6]2[N:7]=[C:8]([C:12]3[S:13][C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=4[C:16](=[O:18])[N:17]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:28][CH2:29][CH2:31][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(-c2cccc(CN3CCCCC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and piperidine (0.081 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.16 g, 54%) as pale yellow crystals.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([S:8][CH3:9])=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30]
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Reactant: CSSC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
Sulfuryl chloride (0.8 mL, 10 mmol) was added to an ice-bath cooled solution of 1.0 mL of dimethyldisulfide in 25 mL of methylene chloride, the cooling bath removed, and the mixture allowed to warm to room temperature. Three mL of this solution (containing methanesulfenyl chloride) was added to 320 mg (1.1 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) in 100 mL of methylene chloride, stirred 0.33 hours, saturated NaHCO3 solution added, stirred well, and the methylene chloride solution separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue chromatographed on silica was eluted with 40% EtOAc/hexane→100% EtOAc to give 115 mg (31% yield) of 5-methoxy-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 195-197° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](C4C=CC([N+]([O-])=O)=CC=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O>C(OCC)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:8][C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: ClCc1ccncc1
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2=NN(C3CCN(Cc4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
Prepared from starting compound A1 and 4-picolylchloride hydrochloride as described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl ether is added and the resulting mixture stirred for 30 min. The precipitate is filtered off and dried. M. p. 196-197° C.
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(C)CCC(=O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b, 2.09 g, 9.17 mmol) was dissolved in acetonitrile (100 mL) and water (50 mL). Ammonium cerium nitrate (503 mg, 0.92 mmol) in water (50 mL) was added and the resulting mixture was heated up to 70° C. and stirred for 1 h. After being cooled down to room temperature, water (100 mL) was added and the mixture was extracted with ether (100 mL×3). The combined organics were washed with water, brine and dried. After concentration, the residue was purified on a column (silica gel, 0-30% ethyl acetate in hexane) which gave ethyl 1-methyl-4-oxocyclohexanecarboxylate (Int-18c) (1.72 g) as an oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C@H:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:8]([C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[O:10])[CH2:33][CH2:34]3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:36]2[CH2:39][CH2:38][CH2:37]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CC[C@H]3CC[C@H](NC(=O)[C@H]4CC[C@H](O)CC4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Trans-4-hydroxycyclohexanecarboxylic acid (1,991 g, 13.81 mmol) was added to a solution of trans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine (4.6 g, 11.51 mmol) in dichloromethane. HATU (2-(3H-1,2,31-triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate, 5.25 g, 13.8 mmol) and diisopropylethylamine (6.03 mL, 34.5 mmol) were added and the mixture stirred at room temperature for 14 h. The solvent was evaporated and the residue partitioned between dichloromethane and water. The aqueous phase was extracted several times with dichloromethane. The combined organic layers were washed twice with 5% aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. Purification via silica gel chromatography (330 g Reveleris NP cartridge) with dichloromethane/methanol (0-80%) as eluent yielded 6.05 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(CCCN2CCCC2)cc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(CCCN3CCCC3)cc2)cc1
Yield: 33 %

Procedure:
By essentially following the procedure outlined in Example 2, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3; Part A) and 4-[3-(1-pyrrolidinyl)propyl]benzoic acid hydrochloride in 33% yield as a viscous oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:14][CH2:15]S(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:20].[Na+]>CC(C)=O>[Si:1]([O:8][C@@H:9]([CH2:14][CH2:15][I:20])[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CCI)O[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
To a solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) in anhydrous acetone was added sodium iodide (11.5 g, 75 mmol). The reaction was heated at reflux for 1.5 h. The reaction was quenched with water and extracted into EtOAc×3. The combined organic phases were washed with brine then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-iodobutanoate (91e, 4.33 g, 12 mmol) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 0.07-0.13 (m, 6H), 0.82-0.99 (m, 9H), 2.09-2.32 (m, 2H), 3.17-3.36 (m, 2H), 3.74 (s, 3H), 4.29 (dd, J=8.08, 4.04 Hz, 1H).