Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=[CH2:32])=[CH:25][CH:24]=1.N1C(C)=CC(C)=CC=1C>ClC(Cl)C>[F:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][C:28]2[CH:29]=[C:30]([CH:31]3[CH2:4][C:3](=[O:5])[CH2:32]3)[CH:33]=[CH:34][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CC(=O)N(C)C
Reactant: C=Cc1cccc(Oc2ccc(F)cc2)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC(Cl)Cl
Product: O=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
To a solution of N,N-dimethylacetamide (1.66 g, 19.1 mmol) in dichloroethane (50 mL) at -15° C., was added trifluoromethanesulfonic anhydride (5.39 g, 19.1 mmol) dropwise and the mixture was stirred for 5 min. A mixture of 3-(4-fluorophenoxy)styrene (4.08 g, 19.1 mmol) and collidine (2.31 g, 19.1 mmol) as a solution in dichloroethane (10 mL) was then added dropwise. Upon completion of addition, the cooling bath was withdrawn and the reaction allowed to warm to ambient temperature, then further brought to reflux for 18 hours. Water (20 mL) was then added and the reaction was kept at reflux for an additional 5 hours. It was then cooled to ambient temperature and the layers were separated. The organic phase was washed with 10% aqueous HCl (50 mL) and water (50 mL). It was then dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; hexanes, ether 90:10) to afford 2.60 g (53%) of 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 27 °C
Reaction time: 22 h
Yield: 91.8 %

Procedure:
(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3.57 g) was added to a mixed solution (35.7 ml) of ethanol and water (97:3), and they were stirred at 27° C. for 22 hours and then at 33° C. for 4 hours. 11.3% aqueous citric acid solution (40.3 g) was added to the obtained mixture, and they were cooled to −10° C. The crystals thus formed were taken by the filtration, washed with water (35.7 ml) and dried under reduced pressure to obtain intended (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) in a yield of 95%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:6]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O)[C:5]([CH3:25])=[N:4]1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:17]([C:6]1[C:5]([CH3:25])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCn1nc(C)c(C(O)c2ccccc2)c1Oc1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(C)c(Cc2ccccc2)c1Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.1 %

Procedure:
A solution containing 54 mg of 1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl-phenyl-methanol and 28 μl of triethylsilane in 2 ml of trifluoroacetic acid was stirred at room temperature for 22 h. The mixture was concentrated and saturated sodium hydrogen carbonate (6 ml) was added. The mixture was extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) for the elution to give 33 mg of 4-benzyl-1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazole as a yellow oil. Mass spectrum (ES) m/z 323 [M+H]+, 364 [M+H+CH3CN]+. 1H NMR (DMSO-d6) 1.19 (t, 3H), 2.00 (s, 3H), 3.46 (s, 2H), 3.70 (s, 3H), 3.80 (q, 2H), 6.82–6.89 (m, 4H), 7.01 (d, 2H), 7.12 (t, 1H), 7.20 (t, 2H).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].O[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>>[CH2:6]([N:7]([CH2:2][CH2:1][OH:3])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:5]
Reactant: CC=O
Reactant: Cc1ccc(NCCO)cc1
Product: CCN(CCO)c1ccc(C)cc1

Procedure:
N-ethyl-N-(2-hydroxyethyl)-p-toluidine (EHPT) was prepared substantially as described above in Example 1, except that acetaldehyde was added to ethylate N-(2-hydroxyethyl)-p-toluidine.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C2C=CC=CC=2)C=CC=CC=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:71](Br)[CH:72]=[CH:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C=CCOC(=O)C)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.[Pd](Cl)Cl.O>[C:74]1([CH:73]=[CH:72][CH2:71][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][CH:7]=2)[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: BrCC=Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(=O)OCC=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(CC=Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
(4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (500 mg, 1.68 mmol, 1.00 equivalents), palladium (II) chloride (15 mg, 5 mol %), bis-diphenylphosphinoethane (50 mg, 5 mol %), bis(pinacolato)diboron (469 mg, 1.85 mmol, 1.10 equivalents), and potassium acetate (495 mg, 5.04 mmol, 3.00 equivalents) were heated in dimethyl formamide (10 mL) at 80° C. for 3 hours. The black reaction mixture was cooled to room temperature. Palladium (II) chloride (15 mg, 5 mol %), bis-diphenylphosphinoethane (50 mg, 5 mol %), cinnamyl bromide (660 mg, 3.35 mmol, 2.00 equivalents), sodium carbonate (890 mg, 8.40 mmol, 5.00 equivalents), and water (4 mL) were added. The reaction mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). This mixture was extracted with saturated sodium bicarbonate (2×50 mL), water (2×50 mL) and brine (50 mL). The organic portion was dried over sodium sulfate. Evaporation of the solvent gave a black oily residue that was chromatographed on Biotage (5% ethyl acetate/hexanes) to give a 9:1 mixture of the title compound and acetic acid 3-phenyl-allyl ester (200 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 3.52 (dd, 2H, J=7, 1.2 Hz), 3.60 (s, 2H), 3.68 (s, 3H), 6.24-6.38 (m, 1H), 6.43-6.47 (d, 1H), 7.1-7.4 (m, 9H). This material was used in example 23C without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.[C:21]([NH:24][CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:75]=[CH:74][C:35]([O:36][CH2:37][C:38]3([O:44][C:45](=[O:73])[CH:46]([NH:62][C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:53])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[C:34]([F:76])[CH:33]=2)[CH2:27]1)(=[O:23])[CH3:22].C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:21]([NH:24][CH2:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:75]=[CH:74][C:35]([O:36][CH2:37][C:38]3([O:44][C:45](=[O:73])[CH:46]([NH:62][C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:53])[CH2:39][CH2:40][N:41]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:42][CH2:43]3)=[C:34]([F:76])[CH:33]=2)[CH2:27]1)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 62 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.25 mmol), 178 mg 2,6-bis-benzyloxycarbonylamino-hexanoic acid 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester hydrochloride (MW: 814.31, 0.22 mmol), 90 mg triethylamine (MW: 101.19, 0.88 mmol) and 48 mg trimethylchlorsilan (MW: 108.64, 0.44 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 94 mg, 42%. MS: 1025.3 (M+H)+, Method ESI+.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)C>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[S:24][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11]
Reactant: Cc1[nH]cnc1CSCCNC(N)=S
Reactant: Cc1[nH]cnc1CSCCCl
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=N)SCCSCc1nc[nH]c1C

Procedure:
1-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane and N-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea are heated together at reflux temperature in ethanol, and the mixture is evaporated and the residue purified to give the title compound, which may be converted into a suitable salt by ion-exchange chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[S:23][CH:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:27][C:25]1[N:26]=[C:22]([CH2:21][O:20][C:16]2[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[N:18][CH:17]=2)[S:23][CH:24]=1
Reactant: Cc1csc(COc2cncc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1csc(COc2cncc(N3CCNCC3)n2)n1
Yield: 98 %

Procedure:
6′-(4-Methyl-thiazol-2-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (I-3u) (376 mg, 0.96 mmol) was dissolved in dry 1,4-dioxane (4 mL) and 4 M HCl in 1,4-dioxane (4 mL, 16 mmol) was added with stirring. A gummy solid immediately precipitated. Methanol (2 mL) was added to solubilize the solid. The resulting solution was stirred at room temperature for 4 h and concentrated to a gummy yellow solid. The residue was basified by addition of 1 M NaOH (15 mL) and extracted with CH2Cl2 (3×20 mL). The combine extracts were dried over Na2SO4 (anhydrous), filtered, and concentrated in vacuo to an amber oil. The oil solified on drying in vacuo to give the title compound 3-Q (274 mg, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:33])[C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:22]=1[NH:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:27][C:25]1[CH:24]=[CH:23][C:22]([NH:30][CH2:31][CH3:32])=[C:21]([CH:26]=1)[C:20]([NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])=[CH:5][C:4]=1[CH3:18])=[O:33]
Reactant: CCNc1ccc([N+](=O)[O-])cc1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: CCNc1ccc(N)cc1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-ethylamino-5-nitrobenzamide (3.0 g, 6.2 mmol) (see Example I5) was dissolved in isopropanol (50 ml) and tin chloride (4.2 g, 22.3 mmol) was added. The mixture was cooled to 0° C. and a solution of concentrated hydrogen chloride (6 ml) was added slowly. The reaction mixture was stirred at 80° C. for 2 hours. Then ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and a solution of aqueous sodium hydroxide (4N) to adjust the pH to 7-8. The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was used without further purification (2.8 g, 100% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl>CCO>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1nccs1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CCO
Product: Oc1cccc(Nc2nccs2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (3.3 mL, 36.6 mmol), 3-aminophenol (3.1 mL, 18.3 mmol) and 37% HCl solution (3.1 mL, 36.6 mmol) in 10% aqueous EtOH solution (30 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 80% yield (2.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:18][CH3:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]#[N:11].CS(C)=[O:22].O.[OH-].[Na+]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)([CH2:18][CH3:19])[C:10]([NH2:11])=[O:22]
Reactant: CS(C)=O
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Temperature: 91 °C
Yield: 79 %

Procedure:
To a 1 liter flask was charged 206.5 g (0.7 mole) of alpha-(2,4-dichlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 500 mL of dimethyl sulfoxide and 200 mL of water. To the stirring solution was added 67.2 g (0.84 moles) of 50% sodium hydroxide. The reaction mixture was heated at 91° C. (steam bath) for 3 hours after which GLC indicated the starting material was consumed. The reaction was cooled to 30° C. then poured into water and extracted with ethyl acetate. After drying, the ethyl acetate was treated with charcoal and filtered through Celite®. Removal of the solvent gave a foamy oil which was stirred and diluted with ethyl acetate then treated with hexane until cloudy. Within 1 hour a solid formed which was cooled at 0° C. The product was filtered and washed with an ether and hexane mixture, then dried and provided 172 g (79% yield) of a white solid, melting point 164°-165° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)(=[O:49])=[O:48])[CH2:9][CH:10]([OH:46])[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1.CC(C)([O-])C.[K+]>O1CCCC1.Cl>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14][CH:13]2[O:12][CH2:11][CH:10]2[CH2:9][N:8]([S:47]([C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)(=[O:49])=[O:48])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:46]2)=[CH:20][CH:21]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(O)CN(c2ccccc2F)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CN(S(=O)(=O)c3ccc(C)cc3)c3ccccc3O2)cc1
Temperature: 25 °C

Procedure:
A solution of 1.04 g tert-butyl 3-{3-[(2-fluorophenyl)(toluene-4-sulphonyl)amino]-2(R,S)-hydroxypropoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.60 g of potassium tert-butoxide in 30 ml of tetrahydrofuran is stirred at reflux over 30 minutes. The reaction mixture is cooled to room temperature, diluted with 1N HCl and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:2 EtOAc-heptane); Rt=6.32.
Reaction SMILES: C(NCC1SC([B:10]([OH:12])[OH:11])=CC=1)C.C(S(N1CCC(C2C3C(=C(C(N)=O)C=C([C:33]4[S:34][C:35]([CH2:38][NH:39][CH2:40][CH:41]([CH3:44])[CH2:42][CH3:43])=[CH:36][CH:37]=4)C=3)NC=2)CC1)(=O)=O)C.C(C1SC(B(O)O)=CC=1)=O.[BH3-]C#N.[Na+].CC(CC)CN>CO>[CH3:44][CH:41]([CH2:42][CH3:43])[CH2:40][NH:39][CH2:38][C:35]1[S:34][C:33]([B:10]([OH:12])[OH:11])=[CH:37][CH:36]=1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: CCNCc1ccc(B(O)O)s1
Agent: CCC(C)CN
Agent: O=Cc1ccc(B(O)O)s1
Agent: [BH3-]C#N
Solvent: CO
Product: CCC(C)CNCc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide was prepared as follows: A solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol) in MeOH (0.5 mL) were added to (2-methylbutyl)amine (28 mg, 0.32 mmol) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 20 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 43 mg of crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid.
Reaction SMILES: [C:1]1([C:7](=[N:14][NH2:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.CN(C)C(N(C)C)=N.C(OO)(=O)C>ClCCl>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(=O)OO
Agent: CN(C)C(=N)N(C)C
Agent: II
Solvent: ClCCl
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To diphenyl ketone hydrazone (19.6 g, 0.1 moles) dissolved in dichloromethane (100 ml) containing iodine (4 ml, 1% w/v solution) and 1,1,3,3-tetramethylguanidine (45 ml) was added peracetic acid solution (23.5 ml, 1.30 × 0.05 moles) at 0° over 60 minutes. The mixture was stirred for an additional 15 minutes. The purple-red solution was washed with water (5 × 250 ml), dried and made up to 500 ml in a volumetric flask. A UV assay on a suitably diluted aliquot corresponded to a yield of diazoalkane of 95.6%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)C.[H][H]>[CH3:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Solvent: CCO
Product: Cc1ncccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 47.4 %

Procedure:
tert-Butyl 4-(2-methyl-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (209 mg, 0.76 mmol) was dissolved in ethanol (42 ml) and hydrogenated in a H-cube hydrogen generator with a flow of 1 ml/min and at a temperature of 70° C. The mixture was evaporated under reduced pressure, the residue was purified by preparative HPLC (Waters X-Bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 100 mg of a colourless solid (0.36 mmol, yield 47%). MS (ESI) m/z=277.2 [M+1]+.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]2=[N:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]4=[N:4][C:3]=3[CH:13]([CH3:15])[CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: COc1cccn2c(I)c(C(C)C)nc12
Product: COc1cccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C(C)C)nc12
Yield: 34.6 %

Procedure:
[step 3] Using 3-iodo-2-isopropyl-8-methoxyimidazo[1,2-a]pyridine (600 mg, 1.90 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (278 mg, 0.95 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[hydroxy(2-isopropyl-8-methoxyimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (159 mg, 35%) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH3:9])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13]>C(COC)OC>[CH3:1][C:2]([CH2:7][CH2:8][CH3:9])([CH2:5][O:6][S:12](=[O:15])(=[O:14])[NH2:13])[CH2:3][O:4][S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CCCC(C)(CO)CO
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC(C)(COS(N)(=O)=O)COS(N)(=O)=O
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 10 g. (0.076 mol.) of 2-methyl-2-propyl-1,3-propanediol in 200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodium hydride followed by an additional 400 ml. of dimethoxyethane. After stirring overnight the suspension is cooled to 4° C and a solution of 31.2 g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethane is added dropwise. The resulting suspension is stirred overnight at room temperature. The mixture is then filtered, the filtrate is concentrated and the residue washed with heptane. The residue is then chromatographed through SilicAR, CC-7 and eluted with 25% acetone-chloroform. The solid obtained after removel of the solvent is crystallized from a mixture of ethyl acetate-hexane-methylene chloride to afford 2-methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol, m.p. 92°-94° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1
Reactant: O=S(Cl)Cl
Reactant: CN1C(=O)C(CCO)Sc2ccccc21
Solvent: ClCCl
Product: CN1C(=O)C(CCCl)Sc2ccccc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 4.90 g of 2-(2-hydroxyethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one in 20 ml of dichloromethane, was added dropwise 5 ml of thionyl chloride with stirring at room temperature. The mixture was stirred for one hour and then concentrated. The concentrate was subjected to a column chromatography on silica-gel (35 g). From the eluate with hexane-ethyl acetate (4:1, v/v) was obtained 5.05 g (95.3%) of 2-(2-chloroethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one as an oily substance.