Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)C(C)(C)C)CC4)nc12
Yield: 105.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.014 g pivaloyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.047 g (88%) 1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-2,2-dimethyl-propan-1-one as yellow solid; MS (ISP): m/e=470 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:6]2[CH:5]=[C:4]([Br:3])[CH:8]=[N:7]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (60% in mineral oil, 1.36 g, 34 mmol) is added portionwise to a stirred solution of 4-bromopyrazole (4.58 g, 30.9 mmol) in DMF (20 ml). The resulting mixture is stirred for 1 h at 0° C. and 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 61, 8.62 g, 30.9 mmol) is added. The resulting pale suspension is heated at 100° C. for 1 h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient hexanes: TBDME from 1:0=>0:1) to afford the title compound as a colorless solid, Rt=1.213 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 330 (M+1, 79Br)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4-[3-(methyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (3.33 g, 12.05 mmol) was placed in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (4.7 g, 1.2 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step D (2.4 g, 9.66 mmol, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 6.68 (s, 1H), 6.63 (s, 2H), 3.81 (s, 3H), 3.52 (bs, 2H), 3.07 (d, J=11.90 Hz, 2H), 2.40 (s, 1H), 2.32-2.38 (m, 2H), 1.98-2.07 (m, 2H), 1.80 (ddd, J=12.32, 6.00, 3.30 Hz, 4H), 1.51-1.61 (m, 2H), 0.91 (t, J=7.42 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:34][CH2:35][CH3:36])[CH2:12][C:13]1[N:17]([CH2:18][CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][C:23]([CH2:25][O:26][Si](C)(C)C(C)(C)C)=[CH:24][C:15]=2[N:14]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:12][C:13]1[N:17]([CH2:18][CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][C:23]([CH2:25][OH:26])=[CH:24][C:15]=2[N:14]=1)[CH2:34][CH2:35][CH3:36])=[O:10]
Reactant: CCCN(Cc1nc2cc(CO[Si](C)(C)C(C)(C)C)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(Cc1nc2cc(CO)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 99.6 %

Procedure:
A solution 1.25 g (2.4 mmole) of (2,5-difluorophenyl)-N-propyl-N-({1-propyl-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]benzimidazol-2-yl}methyl)carboxamide in 20 mL of THF is treated at room temperature with 3 mL of 1M tetrabutylammonium fluoride for 1 hr. The reaction solution is diluted with 20 mL of sat NaHCO3 and extracted with 3×100 mL of dichloromethane. The organic extracts are dried over anhydrous Na2SO4 and the solvent removed in vacuo to afford 0.96 g (99%) of (2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(=O)(=O)(O)O>>[CH:15]1[C:14]([OH:17])=[CH:13][CH:12]=[C:11]([S:8]([C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][CH:2]=2)(=[O:10])=[O:9])[CH:16]=1.[CH:22]1[CH:23]=[C:18]([OH:24])[C:19]([S:8]([C:3]2[CH:4]=[CH:5][C:6]([OH:7])=[CH:1][CH:2]=2)(=[O:10])=[O:9])=[CH:20][CH:21]=1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccccc1O

Procedure:
It is known to prepare 4,4'-dihydroxydiphenylsulfone from phenol and sulfuric acid. This process yields 4,4'-dihydroxydiphenylsulfone along with large quantities of 2,4'-dihydroxydiphenylsulfone as an isomer by-product. However, extreme difficulty is encountered in separating the 4,4'-dihydroxydiphenylsulfone directly from the resulting reaction mixture.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[CH2:6][C:7]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[O:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)([C:12]#[N:13])[CH2:8][CH2:9][C:10]\1=O)C.Cl.[NH2:30][C:31]([NH2:33])=[NH:32].[O-]CC.[Na+]>C(O)C>[NH2:32][C:31]1[N:33]=[CH:4][C:5]2[CH2:6][C:7]([C:14]3[C:22]4[C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[O:19][C:18]=4[C:17]([O:27][CH3:28])=[CH:16][CH:15]=3)([C:12]#[N:13])[CH2:8][CH2:9][C:10]=2[N:30]=1
Reactant: N=C(N)N
Reactant: COc1ccc(C2(C#N)CCC(=O)/C(=C/N(C)C)C2)c2c1oc1ccccc12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2(C#N)CCc3nc(N)ncc3C2)c2c1oc1ccccc12
Temperature: 75 °C

Procedure:
A mixture of the compound obtained in example 6 (100 mg, 0.267 mmol), guanidine HCl (33.5 mg, 0.35 mmol) and sodium ethoxide (25 mg, 0.35 mmol) in 5 ml ethanol was heated at 70-80° C. for 1 hr. The mixture was cooled to room temperature and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography to get 80 mg (81% yields) of a white colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](#[N:12])[CH3:11].[H-].[Na+].C(O)(C)(C)C>O.CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([CH2:11][C:10]#[N:12])=[NH:6]
Reactant: CC#N
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CC(C)(C)O
Product: N#CCC(=N)c1cccc(F)c1

Procedure:
A 1.21 g. portion of m-fluorobenzonitrile, 0.52 ml. of acetonitrile, 0.5 g. of sodium hydride and 0.1 ml. of t-butanol are added to 25 ml. of ether. The mixture is refluxed on a steam bath for one hour. Methanol and water are added. The layers are separated and the aqueous layer is extracted with two 25 ml. portions of ether. The combined ether layers are dried over sodium sulfate, passed through diatomaceous earth, diluted with hexanes and evaporated on a steam bath. The resulting oil is chromatographed using methylene chloride on silica gel giving 0.52 g. of an oil which crystallizes. This material is taken up in methylene chloride. Hexanes are added and the mixture is evaporated, giving an oil with crystallizes. This material is recrystallized from carbon tetrachloride giving the desired product, mp. 67°-68° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Li:20])CCC>C1(C)C=CC=CC=1>[C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:15][Li:20])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Product: [Li]Oc1c(C(C)(C)C)cccc1C(C)(C)C
Yield: 95 %

Procedure:
Both 10 mmol (2.2 g) of monocyclopentadienyl titanium chloride(CpTiCl3) and 100 ml of toluene were added to a 200 ml Schlenk reactor in the atmosphere of inert gas. Then, 10 mmol of 2,6-di-t-butyl phenoxy lithium, so obtained from the reaction between 2,6-di-t-butyl phenol and n-butyl lithium, was slowly added to the mixture. The reactional solution was stirred at room temperature and stood for 1 hour. After 1 hour, some mixture was collected and was analyzed by 1H-NMR spectroscopy to ascertain the reaction results.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](OC2C=CC=CC=2)=[CH:27][CH:26]=1.F>>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:28]3[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: F
Product: Cc1ccc(Oc2ccc(C(c3ccc(C)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
reacting 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane with an aromatic, halogen-containing nitro compound or dinitro compound, or reacting 2-(4-methylphenyl)-2-hexafluoroisopropanol with 4-methyldiphenyl ether in the presence of anhydrous hydrofluoric acid to give 2-(4-methylphenyl)-2-[4-(4-methylphenoxy)phenyl]hexafluoropropane,
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[I-:18].[Na+].O>CC(=O)CC>[I:18][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: ClCCOc1ccc(Cc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: ICCOc1ccc(Cc2ccccc2)cc1
Yield: 72.9 %

Procedure:
A solution of 1-(2-chloroethoxy)-4-(benzyl)benzene (734 mg, 2.97 mmol) and sodium iodide (1.78 g, 11.9 mmol) in 2-butanone (30 mL) was heated at reflux for 16 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 732 mg of 1-(2-iodoethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.11 (d, 2H), 6.84 (d, 2H), 4.23 (t, 2H), 3.94 (s, 2H), 3.41 (t, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9]C)=[CH:7][CH:6]=[C:5]([F:11])[C:3]=1[NH2:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:4][C:3]1[C:2]([Cl:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[F:11]
Reactant: COc1ccc(F)c(N)c1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1c(F)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 2-chloro-6-fluoro-3-methoxy-aniline (0.85 g, 4.84 mmol, 1.0 eq) in DCM (8 mL) at 0° C. was added BBr3 (6.06 g, 24.2 mmol, 5.0 eq). The mixture was stirred at room temperature under N2 overnight, then poured into ice-water. The pH of the solution was adjusted to pH 6 by addition of sat.NaHCO3. The dichloromethane was removed under reduced pressure and the aqueous residue was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a pale yellow solid (0.74 g, 95%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[I-].[CH3:12][N:13]([CH3:36])[CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:37][O:38][C:39](=[O:58])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH:55]=O)=[C:43]([I:57])[CH:42]=1.Cl>C1(C)C=CC=CC=1>[CH3:37][O:38][C:39](=[O:58])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH:55]=[CH:16][CH2:15][CH2:14][N:13]([CH3:36])[CH3:12])=[C:43]([I:57])[CH:42]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2C=O)c(I)c1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(OCc2ccccc2C=CCCN(C)C)c(I)c1
Reaction time: 1 h
Yield: 177.3 %

Procedure:
Potassium bis(trimethylsilyl)amide (KHMDS) (0.5M in toluene, 102.5 ml, 51 mmol) was slowly added to a dispersion of (3-Dimethylamino-propyl)-triphenyl-phosphonium iodide (24.3 g, 51 mmol) in anhydrous toluene (60 ml) at room temperature and in an inert atmosphere. The mixture was stirred at this temperature for 1 hour and then [4-(2-Formyl-benzyloxy)-3-iodo-phenyl]-acetic acid methyl ester (5 g, 12 mmol) in anhydrous toluene was added and was stirred at this temperature for 2 h 30 min. Hydrochloric acid 2N was added to the mixture and organic layers were washed with HCl 2N. Watery layers were washed with toluene and were alkalized with K2CO3. The aqueous layers were extracted with ethyl acetate, were filtered, dried and concentrated to dryness to obtain 10.2 g (73%) {4-[2-(4-Dimethylamino-but-1-enyl)-benzyloxy]-3-iodo-phenyl}-acetic acid methyl ester (72:28 Z/E), that was used, without having been purified in the following step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=2)[CH:11]=1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cn2cc(-c3ncco3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ncco3)ccc2n1
Yield: 80 %

Procedure:
512 mg of ethyl 6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 365 mg of 6-(oxazol-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.O>[CH3:16][S:17]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
Potassium carbonate (324 g, 2340 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform (300 mL) and water (300 mL). The slurry was cooled to 0° C. and treated with methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise addition over a 1 h period (gas evolution was observed). The reaction mixture was allowed to shake for 72 h and was partitioned between CH2Cl2 (500 mL) and saturated aqueous NaHCO3 (500 mL). The aqueous layer was extracted with CH2Cl2 (3×200 mL). The organic layer was washed with 1% KHSO4 (250 mL), dried (Na2SO4), and concentrated to afford 90.5 g (87%) of a white solid. MS (electrospray): exact mass calculated for C6H11NO3S, 177.1; m/z found, 178.1 [M+H]+. HPLC (reverse phase conditions): tR=2.19 min. 1H NMR (400 MHz, CDCl3): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3 Hz, 4H).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=O)[CH2:2]1.[CH3:11][O:12][NH2:13].CC([O-])=O.[Na+]>CCO>[CH3:11][O:12][N:13]=[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1][CH2:2]1
Reactant: O=C1COc2ncccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CON=C1COc2ncccc21

Procedure:
To a solution of furo[2,3-b]pyridine-3(2H)-one (78.3 mmol) [J. Heterocyclic Chem., 23, 1465 (1986)] in 500 mL EtOH were added O-methyl-hydroxylamine (157 mmol) and NaOAc (157 mmol). After heating to reflux for 2 h the reaction mixture was concentrated in vacuo to half of its volume. Water and DCM were added and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (5/1 to 1/1) gives the desired product as yellow oil;
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=2[I:23])=[C:11]([N+:26]([O-])=O)[CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O>P(OCC)(OCC)OCC>[C:1]([O:5][C:6](=[O:29])[N:7]([C:9]1[CH:10]=[C:11]2[C:12]([CH:15]=[C:16]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[I:23])[NH:26]2)=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(I)c1/C=C/c1ccc(N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(N(C)C(=O)OC(C)(C)C)cc2[nH]1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-methyl-carbamic acid tert-butyl ester (1.00 g, 1.96 mmol) in triethyl phosphite (5.0 ml) was refluxed for 3 h. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (550 mg, 59%) as a white solid. MH+ 479.7.
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12]([O:37][CH3:38])=[CH:13][C:14]2[N:20](COCC[Si](C)(C)C)[C:19](=O)[C@@H:18]3[CH2:30][C:31]([CH:33]=[CH2:34])=[CH:32][N:17]3[C:16](=[O:35])[C:15]=2[CH:36]=1.CCO.C1COCC1>O.CO>[CH3:9][O:10][C:11]1[C:12]([O:37][CH3:38])=[CH:13][C:14]2[N:20]=[CH:19][C@@H:18]3[CH2:30][C:31]([CH:33]=[CH2:34])=[CH:32][N:17]3[C:16](=[O:35])[C:15]=2[CH:36]=1
Reactant: C=CC1=CN2C(=O)c3cc(OC)c(OC)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CC1=CN2C(=O)c3cc(OC)c(OC)cc3N=C[C@@H]2C1
Reaction time: 4 h
Yield: 49.8 %

Procedure:
Solid sodium tetraborohydride (NaBH4, 81 mg, 2.175 mmol) was added in one portion to a rapidly stirred solution of 176 (101 mg, 0.233 mmol) in a mixture of anhydrous EtOH (2 mL) and anhydrous THF (4 mL) at room temperature and allowed to stir for 4 h. The reaction mixture was diluted with water (5 mL) and extracted with CHCl3 (3×5 mL). The organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. Filtration and evaporation afforded the crude product, which was stirred for 30 minutes with silica gel (0.25 g) in MeOH (5 mL). Excess methanol was removed by rotary evaporation, causing the crude product to be absorbed onto the silica gel. The plug of silica gel was added to the top of a silica gel column and the product was purified by flash column chromatography eluting with a 60:40 mixture of petroleum ether:EtOAC. Pure fractions were combined and evaporation of the solvent in vacuo afforded the product (177) as a yellow solid (33 mg, 0.116 mmol, 50%). 1H NMR (270 MHz, CDCl3) δ 7.86 (d, 1H, J=3.84 Hz, imine CH), 7.50 (s, 1H, ArH), 7.05 (br s, 1H, H3), 6.82 (s, 1H, ArH), 6.58 (dd, 1H, J=10.62, 17.22 Hz, alkene CH), 5.20-5.05 (m, 2H, alkene CH2), 4.39-4.31 (m, 1H, H11a), 3.96 (s, 3H, OMe), 3.94 (s, 3H, OMe), 3.39-3.12 (m, 2H, H1); 13C NMR (67.8 MHz, CDCl3) δ 162.7, 161.5, 151.9, 147.8, 140.4, 129.9, 126.9, 123.9, 118.9, 114.4, 111.6, 109.8, 77.3, 56.2, 53.9, 33.7.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=3)[OH:11])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=3)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOc1cc(C(O)c2ccc3c(c2)OCO3)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc3c(c2)OCO3)ccc1OC
Yield: 98 %

Procedure:
To a stirred solution of benzo[1,3]dioxol-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanol (1.09 g, 3.6 mmol) in CH2Cl2 (20 mL) at room temperature was added activated MnO2 powder (1.6 g, 18.1 mmol) and kept adding 23 equivalents of MnO2 every 35 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give benzo[1,3]dioxol-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanone as an off-white solid (1.06 g, 98% yield): 1H NMR (CDCl3) δ 1.49 (t, J=7 Hz, 3H, CH2CH3), 3.95 (s, 3H, OCH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 6.07 (s, 2H, CH2), 6.85-6.91 (m, 2H, Ar), 7.32-7.42 (m, 4H, Ar). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.[Cl:11][C:12]1[C:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:12]1[C:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][C:15]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Brc1cnc2ncccn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cc(-c2cnc3ncccn23)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a 50 mL round-bottomed flask was added 3-bromoimidazo[1,2-a]pyrimidine (58 mg, 291 μmol, Syntech, Houston, Tex.), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (120 mg, 291 μmol), tetrakis(triphenylphosphine) palladium (34 mg, 29 μmol), aqueous sodium carbonate (2 M, 0.29 mL, 582 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with CH2Cl2 (5×20 mL). The organic extract was washed with saturated NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2 to give N-(2-chloro-5-(imidazo[1,2-a]pyrimidin-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (68 mg, 58% yield). MS (ESI positive ion) m/z: calcd for C17H11ClFN5O2S: 403.0; found: 403.9 (M+1). 1H NMR (300 MHz, MeOH) δ ppm 7.23 (dd, J=6.94, 4.17 Hz, 1H) 7.25-7.36 (m, 2H) 7.84-7.94 (m, 2H) 8.04 (s, 1H) 8.28 (d, J=2.34 Hz, 1H) 8.52 (d, J=2.19 Hz, 1H) 8.70 (dd, J=4.17, 1.83 Hz, 1H) 8.94 (dd, J=6.94, 1.83 Hz, 1H)