Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]/[CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1/C=C/CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A solution of tert-butyl 4-((E)-3-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}allyl)piperidine-1-carboxylate (0.0308 g, 0.0597 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(E)-3-(piperidin-4-yl)prop-1-enyl]benzofuran-3(2H)-one (0.0173 g, 70%).
Reaction SMILES: CS(C)=O.CC(C)([O-])C.[K+].[SH:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(O[CH2:25][C:26]1[C:31]([CH3:32])=[C:30]([O:33][CH2:34][CH:35]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37][CH2:36]2)[C:29]([CH3:43])=[CH:28][N:27]=1)(=O)C>C1(C)C=CC=CC=1>[CH3:41][C:38]1([CH3:42])[O:39][CH2:40][CH:35]([CH2:34][O:33][C:30]2[C:29]([CH3:43])=[CH:28][N:27]=[C:26]([CH2:25][S:11][C:12]3[NH:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[N:13]=3)[C:31]=2[CH3:32])[CH2:36][O:37]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CC(=O)OCc1ncc(C)c(OCC2COC(C)(C)OC2)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of potassium t-butoxide (262 mg, 2.33 mmol) and 2-mercaptobenzimidazole (349 mg, 2.33 mmol), (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl acetate (500 mg, 1.55 mmol) was added and the mixture was stirred in a nitrogen atmosphere at 150° C. for 3 hours and 10 minutes. After cooled to room temperature, the reaction mixture was diluted with toluene and washed with a diluted aqueous sodium hydroxide solution and a saturated saline solution, dried over sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure. The residue was subjected twice to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1) to obtain the title compound (441 mg, 68.8%) as a white foam.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[C:15]([Si:19]([CH3:22])([CH3:21])[O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(CCO)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol as a colorless oil (2.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]([O:5][C:6](=O)[C:7](Cl)(Cl)Cl)=[O:4]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([Cl:13])([Cl:12])[Cl:1])[CH3:7]
Reactant: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(Cl)(Cl)Cl

Procedure:
Ethanol is reacted with trichloroacetic anhydride to yield ethyltrichloroacetate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27]C3CCCCO3)[C:21]=2[O:20][CH2:19][C:18]1=O)=O.Cl>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: O=C(NCCCN1C(=O)COc2c(OC3CCCCO3)cccc21)c1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Product: Oc1cccc2c1OCCN2CCCNCc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
4-(3-(2-naphthoylamino)propyl)-3-oxo-8-(tetrahydropyran-2-yloxy)-3,4-dihydro-2H-1,4-benzooxazine (398 mg) was dissolved in methanol (5 ml), and a 1N hydrochloric acid aqueous solution was added to the resultant solution, and the mixture was stirred at 0° C. for 1 hour. The reaction solution was extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was dissolved in THF (5 ml). A borane THF complex (1.0 M in THF, 2.8 ml) was added to the resultant solution, and then the mixture was refluxed under heating for 3.5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, and then the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography (silica gel:ethyl acetate/n-hexane=3:7) to obtain the object compound (166 mg, yield 52%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(C1C=C(C)ON=1)(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]Br.[Br-]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1[SH](N)(=O)c1cc(C)on1
Reactant: BrBr
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazole-3-yl)-aminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.61 g; 0.01 mole) was dissolved in chloroform (120 mL), bromine on a polymer carrier (12.5 g; the content of bromide bound to the polymer matrix with polyvinylpyrrolidone was 26%, 0.02 mole) (prepared according to J. Johar, M. Zupan and B. Sket, J. Chem. Soc. Perkin Trans. I, 2059, (1982)) was added and it was stirred for 12 hours at room temperature. The polymer was sucked off and the filtrate was evaporated to dryness. The obtained product was passed through a Merck 60 silica gel column with methylene chloride and thereafter 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (2.36 g, 47.6%) was isolated, m.p. 68°-70° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:58]/[H])/[NH:56]O)=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:58][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: [H]/N=C(\NO)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at RT for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)-propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)CC(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 216 mg of tert-butyl (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoate in 2 ml of dichloromethane was added 2 ml of trifluoroacetic acid, followed by stirring overnight. The solvent was evaporated under reduced pressure, and water, a saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid, and chloroform were added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 147 mg of (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoic acid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([CH:4]([NH2:1])[CH3:5])[N:7]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC(N=[N+]=[N-])c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CC(N)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Yield: 101.9 %

Procedure:
To a solution of 2-(1-azidoethyl)-6-chloro-1-(3-fluorophenyl)-1H-indole (55 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.26 mL, 0.26 mmol) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the desired amine (50 mg). The crude product was used directly in the next step. LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:9])[N:8]=[CH:18][CH:13]=[CH:14]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1cc2ncccc2cc1Br

Procedure:
A mixture of 4-bromo-3-fluoro-phenylamine (2.85 g, 15 m mole), ferrous sulfate (0.95 g), glycerol (5.658 g, 4.5 ml), nitrobenzene (1.125 g, 0.93 ml) and concentrated sulfuric acid (2.61 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 7 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=8/1) to return compound title as white crystals (1.44 g, 42.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[O:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([Mg]Br)[CH2:27][CH2:26]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Solvent: C1CCOC1
Product: OC(c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
5,6-bis(Benzyloxy)pyridazine-3-carbaldehyde (Intermediate 63; 0.5 g, 1.562 mmol) was dissolved into THF (10 ml) and cooled to 0-5° C. under a nitrogen atmosphere. A solution of cyclopropyl magnesium bromide in THF (0.5 M, 4.7 ml, 2.34 mmol) was added at 0-5° C., and reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction was quenched by addition of ethyl acetate and saturated aqueous ammonium chloride solution and extracted into ethyl acetate (2×50 ml). The combined organics were separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude compound was purified by column chromatography (silica, 0-2% methanol in dichloromethane) to afford (5,6-bis(benzyloxy)pyridazin-3-yl)(cyclopropyl)methanol (0.35 g, 61.9% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][N:12]([CH3:14])[C:11](=O)[CH2:10][CH2:9]1.O.[OH-].[Na+]>O1CCCC1.COC(C)(C)C>[CH:16]1([C:8]2([NH2:7])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CN1CC(N)(C2CCCCC2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CN1CCCC(N)(C2CCCCC2)C1
Temperature: 65 °C
Yield: 87.2 %

Procedure:
To 2.06 ml of a 2.5M lithium aluminium hydride solution in tetrahydrofuran cooled to 0° C. was added dropwise a solution of 452 mg (2.15 mmol) rac-5-amino-5-cyclohexyl-1-methyl-piperidin-2-one in 6 ml tetrahydrofuran. Then the solution was heated to 65° C. for 1 hour. The turbid reaction solution was cooled with an ice bath and below 12° C. were added drop-wise 0.13 ml water, 0.32 ml 2N NaOH and further 0.19 ml water. The suspension was diluted with tert-butyl methyl ether, dried over sodium sulfate, filtered and evaporated: 368 mg title compound were obtained as colourless oil which was used without purification for the next step.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>C(#N)C>[CH2:27]([N:29]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:30][CH3:31])[CH3:28]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(CC)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-ethylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 84 (2), 58 (5).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C(C1CCCCN1C)C#C.[CH2:29]1[CH2:39][CH2:38][N:37]2[C:32](=N[CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30]1>CC(N(C)C)=O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][CH:32]1[CH2:30][CH2:29][CH2:39][CH2:38][N:37]1[CH2:36][C:35]#[C:34][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: C#CCC1CCCCN1C
Solvent: CC(=O)N(C)C
Product: CC1CCCCN1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 120 °C
Reaction time: 10 h
Yield: 63.3 %

Procedure:
A flask was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (250 mg, 0.76 mmol), 2-propargyl-1-methyl-piperidine (105 mg, 0.76 mmol), copper iodide (15 mg, 0.076 mmol), dichlorobis-(triphenylphosphine)palladium (II) (11 mg, 0.02 mmol) and DBU (0.34 mL, 2.28 mmol) in dry dimethyl acetamide (3 mL). The mixture was vacuum degassed and heated to 120° C. and stirred for 10 hours. The mixture was cooled to ambient and quenched via the addition of water (45 ml) and ethyl acetate (45 ml). The material was shaken in a separatory funnel, and the ethyl acetate phase was collected. The aqueous phases were back extracted with ethyl acetate (2×40 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC using 15% ethyl acetate in hexanes as eluant. The plates were re-developed consecutively with 40% and then 60% ethyl acetate in hexanes. The product band was collected to provide 185 mg of (+/−)-2-[3-(2-methyl-piperidin-1-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a golden yellow oil. MS (M+H)+=385
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:58])([F:57])[F:59])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 0 °C
Yield: 42.1 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-trifluoromethyl-pyridine (147 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide (122 mg, 43%) as a white foam: EI-HRMS m/e calcd for C20H22 ClF3N2O3S (M+) 474.0992, found 474.0990.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)cc1

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-4-methoxybenzamide was prepared from p-anisoyl chloride (16 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 46 mg, 94 μmol, 83%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; R′, =3.17 min.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[C:8]=2[CH2:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.O/[N:34]=[C:35](\[NH2:45])/[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:14][N:45]=[C:35]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][CH:37]=4)[N:34]=3)[C:8]=2[CH2:15][CH2:16][CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(C(=O)O)noc1-c1ccccc1
Reactant: N/C(=N\O)c1ccc(CCO)cc1
Agent: Fc1nc(F)nc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(-c2nc(-c3ccc(CCO)cc3)no2)noc1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 128 %

Procedure:
To a mixture of 5-phenyl-4-propylisoxazole-3-carboxylic acid (385 mg, 1.665 mmol) and pyridine (0.135 mL, 1.665 mmol) in DCM (5 mL) was added cyanuric fluoride (0.141 mL, 1.665 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with dichloromethane and washed with 1M HCl. The organic layer was dried MgSO4, filtered and concentrated. This crude residue was dissolved in acetonitrile (5.00 mL). (Z)—N′-hydroxy-4-(2-hydroxyethyl)benzimidamide (300 mg, 1.665 mmol) and DIEA (0.582 mL, 3.33 mmol) were added. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried MgSO4, filtered, and concentrated to yield 800 mg of 2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol. MS (m+1)=376. HPLC Peak RT=2.09 minutes. (Analytical Method B).