Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[F:2][CH:3]([F:22])[O:4][C:5]1[CH:6]=[C:7]([C:12]([O-])=[CH:13][C:14](=O)[C:15]([O:17]CC)=[O:16])[CH:8]=[C:9]([F:11])[CH:10]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][NH2:53])[CH:47]=1>>[F:11][C:9]1[CH:8]=[C:7]([C:12]2[N:52]([C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)[N:53]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:6]=[C:5]([O:4][CH:3]([F:2])[F:22])[CH:10]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(OC(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
590 mg (1.01 mmol) of the compound of Example 7A is reacted analogously to the synthesis of the compound of Example 20A with 161 mg (1.11 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 150 mg (43% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N+:44]([O-:46])=[O:45])=[C:39]([CH:43]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:40](=[O:41])[C:39]3[CH:43]=[C:35]([Cl:34])[CH:36]=[CH:37][C:38]=3[N+:44]([O-:46])=[O:45])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
1.86 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1 ml of triethylamine are dissolved in 15 ml of methylene chloride, and 1.27 g of 5-chloro-2-nitrobenzoyl chloride are added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. Then, the extract is evaporated to remove solvent, and the residue is crystallized with ethanol. 2.45 g of (+)-cis-2-(4-methoxyphenyl)-3-(5-chloro-2-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless prisms. Yield: 88.1%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2nc(N3CCOCC3)c3oc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure E to give, after purification by reverse HPLC, 29 mg of 239. MS (Q1) 489 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]2[N:10]([C:14]([CH2:18][C:19]#[CH:20])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH3:29].O>CN(C)C=O>[CH3:17][C:15]1[N:16]=[C:9]2[C:8]([O:7][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[CH3:29])=[CH:13][CH:12]=[CH:11][N:10]2[C:14]=1[CH2:18][C:19]#[CH:20]
Reactant: C#CCc1c(C)nc2c(O)cccn12
Reactant: Cc1cnccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3ccncc3C)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
Potassium carbonate (0.52 g) was added to a solution of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.5 g) and 4-chloromethyl-3-methylpyridine (0.53 g) in N,N-dimethylformamide (10 ml). The mixture was stirred under a nitrogen atmosphere for 5 hours at room temperature and then poured into water. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate to give 2-methyl-8-(3-methyl-4-pyridylmethoxy)-3-(2-propynyl)imidazo[1,2-a]pyridine (0.58 g).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([Br:23])=[CH:20][N:19]=[C:18]([NH2:24])[C:17]=2[N:16]=[C:15]1[CH2:25][CH2:26][CH3:27].[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[NH2:24][C:18]1[C:17]2[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:22]=2[C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CCCc1nc2c(N)ncc(Br)c2n1CCOCCN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)ncc(Br)c2n1CCOCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
Triethylamine (0.07 g, 0.66 mmol) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-7-bromo-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.15 g, 0.44 mmol) in dichloromethane (2 mL). 4-Chlorobenzoyl chloride (0.09 g, 0.53 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at ambient temperature for 10 minutes at which time analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was partitioned between dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The layers were separated. The organic layer was washed sequentially with saturated aqueous ammonium chloride (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide 0.23 g of a clear, glassy solid. The crude material was purified by chromatography (silica gel eluting with 95:5 dichloromethane:methanol) to provide 0.05 g of N-{2-[2-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-4-chlorobenzamide as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[C:21]([CH3:28])[C:19]=2[N:20]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:25]([C:23]3[CH:22]=[C:21]([CH3:28])[C:19]4[N:20]=[C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])[NH:17][C:18]=4[CH:24]=3)=[O:27])=[CH:42][CH:43]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)O)cc3[nH]2)c1
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: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3c(C)cc(C(=O)Nc4ccc(CCN5CCN(C)CC5)cc4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a solution of the crude of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-7-methyl-3H-benzoimidazole-5-carboxylic acid (estimated 0.4 mmol), 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (88 mg, 0.4 mmol) and HATU (167 mg, 0.44 mmol) in DMF (5 mL) was added DIEA (0.5 mL, 371 mg, 2.87 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 15 h, and then evaporated to dry under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (34.5 mg, 11% from two steps from 3,4-diamino-5-methyl-benzoic acid). 1H NMR (MeOH-d4) δ 2.77 (s, 3H), 2.90 (s, 3H), 2.97-3.43 (12H), 3.97 (s, 3H), 7.09 (m, 1H), 7.22 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.82-7.84 (2H), 7.91 (s, 1H), 8.17 (m, 1H), 8.20 (s, 1H), 8.31 (s, 1H). ESI-MS m/z 577.5 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:22](Cl)(=[O:24])[CH3:23].Cl>[N+](C1C=CC=CC=1)([O-])=O>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1([C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH2:9]1
Reactant: FC(F)(F)Oc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)C1(OC(F)(F)F)C=CC(c2ccccc2)=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 30 g (126 mmol) 4-(trifluoromethoxy)-1,1′-biphenyl and 21 g aluminium trichloride (157 mmol) in 120 ml nitrobenzene are added at a temperature below 20° C. 9.87 g (126 mmol) acetyl chloride. The reaction mixture is stirred for 2 h at 0° C., added to 240 ml ice-water and 42 ml conc. HCl and extracted with ethyl acetate. The organic phase is washed with water and brine and the solvents removed in vacuo. The residue is triturated with petrol ether, filtrated and dried. From the filtrate another batch can be obtained after crystallizing at 4° C. to give overall 23.5 g (66%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)=[NH:4].N1C=CC=CC=1.C(C(CCCC)[CH2:44][O:45]C(Cl)=O)C>CN(C)C=O>[O:45]=[C:44]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][N:20]4[S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=3)=[O:13])=[CH:7][CH:6]=2)[NH:4]1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (254 mg, 0.51 mmol) in dimethylformamide (3.5 ml) was treated with pyridine (0.04 ml, 1 equiv.) and the mixture was cooled to 0° C. Chloroformic acid 2-ethylhexyl ester (98 mg, 0.51 mmol, 1 equiv.) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then quenched with water. The slurry was extracted three times with ethyl acetate. The combined organic layers were dried with Na2SO4 and the solvent was evaporated. The crude compound was suspended in xylene and heated at reflux for 2 hours. After cooling to room temperature, the solid was filtered and dried under high vacuum, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide as a white solid, 114 mg (43%). MS (ISP): m/e=525.2 (M−H), δH (300 MHz; d6-DMSO) 10.31 (1H, s), 7.55-7.80 (8H, m), 7.28 (1H, d), 7.16 (1H, d), 4.04 (2H, t), 3.60 (3H, s), 3.06 (2H, t).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]/[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
E-(R)-1-(2-((2-(2-Methylphenyl)-2-phenylethenyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (1.1 g, 0.0028 mol, prepared similarly to the method described in Example 50) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.7 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid solution (ca. 1.0 ml) was added (with cooling) followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to provide the title compound (0.70 g, 62%).
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.[Na].[Si:9](Cl)([CH3:12])([CH3:11])[CH3:10].Cl>COCCOCCOC.O>[Si:9]([CH2:7][CH:1]([Si:9]([CH3:12])([CH3:11])[CH3:10])[Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: COCCOCCOC
Product: C[Si](C)(C)CC([Si](C)(C)C)[Si](C)(C)C
Temperature: 115 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
In a 500 ml three-necked standard taper joint round-bottomed flask were combined 12.2 g (0.53 mol) of Na metal chunks and 201.8 g of anhydrous diglyme. Flask was fitted with an electric heating mantle, mechanical stirrer (stainless steel blade), addition funnel, Dewar condenser (containing toluene cooled by immersion coil through which ice water was circulated), thermometer, and valves to maintain an inert atmosphere (nitrogen). Heat was applied, melting the sodium, and addition of a mixture of 54.8 g (0.5 mol) of Me3SiCl and 24.3 g (0.24 mol) of CH2 =CHSiMe3 begun at 115°, and continued, with continuous heating, at a rate which maintained the reflux temperature above 98°. Heating at reflux (115° C.) continued for 8 hr, and standing at room temperature for 32 hr, followed by termination by slow addition of a solution of 16.0 g H2O in 57.7 g diglyme and neutralization with 5 g conc HCl in 26.8 g diglyme. Salts were removed by filtration, and the organic layer vacuum distilled, yielding 4.65 g (7.9%) of Me3SiCH2CH(SiMe3)2, identified by VPC/NMR, plus 39.6% of Me3SiOSiMe3 and 6.2% of Me3SiSiMe3.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 85%), MS (ISP) m/z=322.4 [(M+H)+], mp 316.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:19])=[O:18]
Reactant: CCCCC(O)CSc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(CSc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 42.0 g (0.172 mole) of 1-(p-chlorophenylthio)hexan-2-ol and 21.6 g (0.189 mole) of methane sulfonyl chloride in 100 ml of toluene is slowly added 20.8 g (0.206 mole) of triethylamine over a 1/2 hour period at less than 15° C. When the addition is completed, the mixture is stirred for 1/2 hour, and is allowed to warm to ambient temperature.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=O)(=[O:28])=[O:27].Cl.[NH:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:39]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)=[O:34])(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: O=C1CCNCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(C(=O)N2CCC(=O)CC2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
PyBrOP™ (17.3 g) was added to a stirred mixture of 3-methanesulphonyl benzoic acid (7.35 g), 4-piperidone hydrochloride (5 g) and Hunig's base (25 ml) in dichloromethane (250 ml) with stirring at RT. The mixture was stirred overnight then washed with saturated NaHCO3 solution (200 ml) and then with saturated brine (200 ml). The organic layer was evaporated and the resulting residue purified by column chromatography (silica, 1:1 ethyl acetate: dichloromethane) to give the product as a thick oil (9.6 g; MS: APCI+(M+H) 282).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:23]#[N:24])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.N[OH:28].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:23]([NH2:24])=[O:28])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C(N)=O
Reaction time: 4 h

Procedure:
1 ml dry MeOH was added to 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (Example 1, 4.5 mg, 0.01 mmol) under nitrogen followed by 10 eq hydroxylamine hydrochloride. 10 eq NaOMe was added and the mixture was stirred for 4 h. The solvent was concentrated and the crude product was purified on silica using CH2Cl2/MeOH (97:3 to 96:4) as eluents. 2.10 mg 2-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (E2) ES/MS m/z: 363.5 (M+H), 361.6 (M−H); 1H NMR (MeOD, 500 MHz): 7.65 (m 1H), 7.60 (m, 1H), 7.29 (m, 1H), 7.18 (m, 1H), 7.12 (m, 2H), 6.79 (m, 2H), 2.12 (s, 3H), 1.99 (s, 3H) and 1.90 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carboxamide (E3) ES/MS m/z: 348.2 (M+H), 346.3 (M−H); 1H NMR (MeOD, 500 MHz): 7.93 (m 1H), 7.61 (m, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.08 (m, 2H), 6.81 (m, 2H), 2.07 (s, 3H), 2.03 (s, 3H) were obtained as white solids. For Example 2, the title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:34]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C/C=C/c1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Yield: 93.7 %

Procedure:
(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8, 1.74 g, 3.0 mmol) was dissolved in a 1:1 (v:v) THF/MeOH solution. Pd/C (10% wet, 174 mg) was added and the reaction hydrogenated at 40 psi for 3 hours. The reaction was monitored by 1H NMR. Upon completion, the reaction was filtered over Celite with excess MeOH. Removal of solvents in vacuo provided the product as a light yellow solid (1.65 g, 94% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11-7.20 (m, 2 H), 7.07 (t, J=7.8 Hz, 3 H), 6.99 (d, J=8.1 Hz, 2 H), 5.33 (dd, J=9.6 Hz, 1 H), 5.21 (dd, J=9.6 Hz, 1 H), 5.12 (dd, J=9.6 Hz, 1 H), 4.52 (d, J=9.9 Hz, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 3.85-4.00 (m, 2 H), 3.67 (s, 3 H), 2.61 (t, J=7.6 Hz, 2H), 2.33 (t, J=7.5 Hz, 2 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.93 (quin, J=7.6 Hz, 2 H), 1.75 (s, 3 H). MS (ES+) [M+NH4]+=604.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(2-Thienyl)-L-alanine (2.24 g., 13.1 mmol.) was suspended in water/p-dioxane (20 ml./10 ml.) at room temperature under argon. Sodium carbonate (1.39 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (2.87 g.) was added, and the resulting mixture was stirred for 4.5 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 2.70 g. of the title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-153.6° (c= 0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.5.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=C[CH:9]=1.C(C(=O)C(=NO)C)C.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH:32]=[O:33]>>[I:1][CH2:2][C:3]1[N:4]=[C:32]([C:31]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:30]=2[CH3:29])[O:33][C:7]=1[CH2:8][CH3:9]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: Cc1cccc(C)c1C=O
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2c(C)cccc2C)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, 1-ethyl-1,2-propanedione-2-oxime and 2,6-dimethylbenzaldehyde gave 4-iodomethyl-5-ethyl-2-(2,6-dimethylphenyl)oxazole.