Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][C:30]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[C:29]2[C:40](OC)=[O:41])=[CH:24][CH:23]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][OH:18])=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH:32]=[CH:31][C:30]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[C:29]2[CH2:40][OH:41])=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Reactant: COC(=O)c1c(C(F)(F)C(F)(F)F)ccn1-c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)C(F)(F)F)ccn1-c1ccc(Cl)cc1
Product: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed methyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate and methyl 1-(4-chlorophenyl)-3-(perfluoroethyl)-1H-pyrrole-2-carboxylate (200 mg, 0.66 mmol, 1.00 equiv), LAH (50 mg, 1.32 mmol, 2.00 equiv) and tetrahydrofuran (5 mL). The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with ethyl acetate (5×10 mL) and the organic layers combined. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to yield [1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methanol and (1-(4-chlorophenyl)-3-(perfluoroethyl)-1H-pyrrol-2-yl)methanol as yellow oil.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]([Br:9])=[CH:5][N:4]=[CH:3]1.C1([Mg]Br)C=CC=CC=1.[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:9][CH:6]1[C:7](=[O:8])[C:2]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][N:4]=[CH:5]1
Reactant: O=Cc1ccccc1
Reactant: O=C1C(Br)=CN=CC1Br
Agent: Br[Mg]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C(C(O)c2ccccc2)=CN=CC1Br
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of 3,5-dibromo-pyridin-4-one 10 (0.313 g, 1.24 mmol) in anhydrous THF (4 mL) at −78° C. under nitrogen atmosphere was added phenylmagnesium bromide solution (1.36 mL of 1 M solution in THF, 1.36 mmol) [Borzilleri, et al., U.S. Pat. 20050245530]. After stirring for 15 min, n-BuLi solution (0.68 mL of 2 M solution in cyclohexane, 1.36 mmol) was added and the reaction mixture stirred for 15 min at −78° C. under nitrogen atmosphere. To this mixture was added benzaldehyde (0.26 mL, 2.6 mmol) and the mixture was stirred for 2 h at −78° C. The reaction mixture was quenched by adding HOAc (0.38 mL) and TFA (0.38 mL), concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (dichloromethane:methanol, 95:5). Yield 0.125 g (36%), white solid, 123-124° C. 1H NMR (MeOH— d4, 500 MHz): δ 8.09 (s, 1H), 7.81 (s, 1H), 7.38-7.17 (m, 5H), 5.92 (s, 1H), 3.83 (s, 2H). 13C NMR (MeOH— d4, 125 MHz): δ 174.3, 144.4, 139.7, 135.8, 133.6, 129.4, 129.3, 128.6, 128.0, 128.0, 114.8, 70.8.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[O:14][N:13]=1)=O)(C)(C)C.[CH2:25](I)[CH3:26]>>[ClH:23].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:25][CH3:26])[C:18]=2[Cl:24])[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2Cl)on1
Reactant: CCI
Product: CCc1c(Cl)ccc(-c2cc(OCCN)no2)c1Cl
Product: Cl
Yield: 78 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazole (0.3 g) and ethyl iodide (0.1 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.25 g, 78%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1ccc(Br)cc1Oc1ccccc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 250 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with 4-bromo-2-fluorobenzaldehyde (2.00 g, 9.85 mmol, 1.00 equiv), phenol (0.926 g, 9.84 mmol, 1.00 equiv), potassium carbonate (1.35 g, 9.77 mmol, 0.99 equiv), and N,N-dimethylacetamide (30 mL). The resulting solution stirred for 4 h at 150° C. and then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/99) to provide 2.40 g (88% yield) of 4-bromo-2-phenoxybenzaldehyde as a light yellow solid. 1H NMR 400 MHz (CDCl3) δ 10.51 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.41-7.48 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.25-7.29 (m, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.04 (s, 1H). LCMS (ESI, m/z): 277 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[N:5]([P:6](=[O:11])([O-:10])[O:7][CH2:8][CH3:9])[C:4](=[O:12])[C@H:3]1[NH:13]C(OC(C)(C)C)=O.[K].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C1(OC)C=CC=CC=1.C1(C)C=CC=CC=1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:13][C@H:3]1[C@H:2]([CH3:1])[N:5]([P:6](=[O:10])([OH:11])[O:7][CH2:8][CH3:9])[C:4]1=[O:12]
Reactant: CCOP(=O)([O-])N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Agent: [K]
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(O)N1C(=O)[C@@H](N)[C@@H]1C
Temperature: -24 °C
Reaction time: 3 h

Procedure:
A suspension of (3S-trans)-[4-methyl-2-oxo-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]phosphonic acid, ethyl ester, potassium salt (500 mg) in anisole (5 ml) was cooled to -24° C. in an ice-methanol bath, and trifluoroacetic acid (10 ml) was added. The mixture was stirred at -24° C. to -12° C. for 3 hours, diluted with dry toluene (25 ml), and solvent was removed in vacuo at or below 19° C. The residual oil was solidified and triturated several times with ether giving 815 mg of the title compound as a powder.
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:13]1[O:16][CH:14]1[CH3:15]>>[CH:1]1([CH:14]([CH3:15])[CH:13]=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][CH:14]1[O:16][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:1]2[CH2:15]1
Reactant: CC1CO1
Reactant: C1=CCCCCCCCCCC1
Product: CC(C=O)C1CCCCCCCCCCC1
Product: CC1CC2CCCCCCCCCCC2O1

Procedure:
A method according to claim 1, wherein Cyciododecene and propylene oxide are reacted to produce 2-(cyclododecyl)propan-1-al and 2-methylperhydro-cyclododeca[b]furan.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[CH:13]([C:14](=[O:15])[C:6]=2[CH:5]=1)[CH2:12][N:11]([CH3:16])[CH2:10]3.O>C(O)C>[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[CH:13]([CH:14]([OH:15])[C:6]=2[CH:5]=1)[CH2:12][N:11]([CH3:16])[CH2:10]3
Reactant: CN1CC2Cc3ccc(Cl)cc3C(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CC2Cc3ccc(Cl)cc3C(O)C2C1
Temperature: 25 °C

Procedure:
1.6 g of sodium borohydride in 20 ml of ethanol are added at 0°-5° to a solution of 10 g of 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-one in 100 ml of ethanol, stirred at room temperature for a further hour, water is added and the mixture evaporated. The residue is taken up in 10% tartaric acid, the aqueous phase extracted with ether, mixed with 2 N caustic soda solution and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and evaporated. The residue is crystallised from methylene chloride/pentane to yield 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-ol. M.P. 178°-182°.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:4]=2[CH:3]=1.[CH3:13]CCCCCC>>[CH3:12][C:10]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:7]([CH3:13])[CH:2]=[CH:3][C:4]=2[CH:11]=1
Reactant: CCCCCCC
Reactant: Cc1ccc2ccc(C)cc2c1
Product: Cc1ccc2cc(C)ccc2c1
Temperature: 80 °C

Procedure:
A mixture of DMN isomers containing 2% by weight of 2,7-DMN, etc. as shown in Table 3 as the starting raw material was isomerized under liquid-phase flow system and atmospheric pressure at a reaction temperature of 220° C. at a WHSV of 1.0 hr-1 in the presence of a catalyst (alumina content of 20% by weight) prepared by molding with alumina, mordenite type H (silica/alumina molar ratio of 203, produced by Tosoh Corporation). The resultant isoiverization reaction product shown in Table 3 as reaction product (1) was incorporated with the same amount of n-heptane, heated to 80° C. to dissolve the reaction product and then cooled to 20° C. to precipitate crystal. The slurry containing the crystal was filtered by suction with a G2 glass filter, and the crystal thus obtained was rinsed with n-heptane cooled to 20° C. in an amount by weight half the reaction product. As a result, there was obtained 2,6-DMN crystal having the chemical composition given in Table 3 as "Crystal (1)" in a recovery rate of 64.2%. Here, the recovery rate is the percentage of the amount of 2,6-DMN in the resultant crystal based on the amount thereof in the starting raw material for crystallization.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16].[OH-].[K+].O1CCOCC1>CCOCC>[CH2:5]([O:4][C:2]([O:12][N:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC(=NO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#CC(=NOC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
A solution of benzyl chloroformate (5.1 g.) in ether (40 ml.) was added to a solution of 2-hydroxyimino-2-phenylacetonitrile (4.4 g.) in a mixture of a 1N potassium hydroxide aqueous solution (30 ml.) and dioxane (10 ml.) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and for 4 hours at room temperature. The ether layer was separated from the reaction mixture and the aqueous layer was further extracted with ether. Both ether layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off and n-hexane was added to the residue. The precipitated crystals were collected by filtration to give 2-benzyloxycarbonyloxyimino-2-phenylacetonitrile (5.2 g.), mp 73° to 75° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH:42]1[C:46]([C:47]2[CH:48]=[C:49]([C:59](O)=[O:60])[CH:50]=[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH:52]=2)=[N:45][N:44]=[N:43]1>O.CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:14][CH2:15][N:16]([C:59]([C:49]4[CH:50]=[C:51]([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:52]=[C:47]([C:46]5[NH:45][N:44]=[N:43][N:42]=5)[CH:48]=4)=[O:60])[CH2:17][CH2:18]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5ccccc5)cc(-c5nnn[nH]5)c4)CC2)O3)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (93 mg), 1-hydroxybenzotriazole monohydrate (36 mg), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (57 mg), triethylamine (0.73 mL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 5-(tetrazol-5-yl)biphenyl-3-carboxylic acid (50 mg), and stirred at 90° C. for 2 hours and 30 minutes. Water was added to the reaction liquid, and the formed precipitate was taken out through filtration, washed with hexane/ethyl acetate=3/2, and dried to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.36 (1.0H, s), 8.13 (1.0H, s), 8.03 (1.0H, s), 7.85-7.77 (6.0H, m), 7.53 (2.0H, d, J=7.2 Hz), 7.44 (1.0H, t, J=7.2 Hz), 7.10 (1.0H, d, J=8.4 Hz), 4.40-4.22 (1.0H, m), 3.83 (3.0H, s), 3.65-3.20 (3.0H, m), 2.89 (2.0H, s), 2.15-2.05 (1.0H, m), 1.95-1.78 (3.0H, m). MS [M+H]+=546.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)[CH:3]=[N:2]1.Cl[CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:48][N:47]([CH3:49])[CH2:46][CH2:45][CH2:44][N:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)[CH:3]=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 107.1 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (43 mg, 0.07 mmol) and 3-chloro-N,N-dimethylpropan-1-amine (47 mg, 0.39 mmol) were dissolved in DMF (3 ml) and cesium carbonate (240 mg, 0.74 mmol) was added. After stirring the mixture at 75° C. for 3.5 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with dichloromethane (×3). The organic phase was successively washed with water and brine, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure, to obtain 50 mg (70% yield) of the title compound as a brown solid. Purity 69%.
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:8]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:11])[C:9]#[N:10])=[CH:14][CH:15]=1
Reactant: N#CCC(=S)N1CCOCC1
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.122 g, 0.72 mmol) and p-anisaldehyde (0.1 mL, 0.86 mmol) in 10% piperidine/ethanol (5.5 mL) was allowed to stir at 50° C. under nitrogen for 3.5 h. The reaction mixture was concentrated and the residue was diluted with 10% citric acid solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile. The crude product was a mixture of stereoisomers and was used directly in the next step. LCMS: (AA) ES+ 289.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([O:40][C:41](=[O:42])[NH:43][C@H:44]1[CH2:48][CH2:47][N:46]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:45]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1

Procedure:
Following the same procedure in Example 1, step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (2 g, 5 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (1.4 g, 7.5 mmol) in (10 mL) methylene chloride. The crude product was purified by MPLC on silica gel using 8-70% EtOAc/hexane. Yield: 2.77 g (100%). 1H NMR (400 MHz, METHANOL-D4) δ 1.35 (s, 9 H) 1.52 (d, J=11.72 Hz, 4 H) 1.58 (s, 9 H) 1.62-1.73 (m, 4 H) 1.75-1.81 (m, 1 H) 1.93-2.00 (m, 1 H) 3.03-3.10 (m, 1 H) 3.24-3.29 (m, 2 H) 3.35-3.47 (m, 3 H) 4.40 (d, J=7.42 Hz, 2 H) 7.71-7.78 (m, 2 H) 8.09 (d, J=1.37 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]1[C:14]([NH:23][S:24]([C:27]2[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=2)(=[O:26])=[O:25])=[N:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.[C:45]([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])([O:47][CH2:48][CH:49]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]2[C:50]1=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46].O>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH:51]1[C:50]2[CH:49]([CH2:48][O:47][C:45]([NH:62][C@H:63]([C:67]([O:1][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[NH:12][C:13]3[C:14]([NH:23][S:24]([C:27]4[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=4)(=[O:26])=[O:25])=[N:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:22]=3)=[O:68])[CH:64]([CH3:65])[CH3:66])=[O:46])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1
Reactant: COc1ccc(CCO)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCOC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a suspension of N-(3-{[2-(2-hydroxyethyl)-5-methoxyphenyl]amino}quinoxalin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide (200 mg; 0.44 mmol; 1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92.8 mg; 0.48 mmol; 1.1 eq) and N,N-dimethylpyridin-4-amine (59 mg; 0.48 mmol; 1.1 eq) in a mixture of DCM (10 mL) and DMF (1 mL) is added fmoc-l-valine (164 mg; 0.48 mmol; 1.1 eq). The reaction mixture is stirred for 18 h at room temperature. Water is added and organic phase is washed several times with 10% citric acid then dried under MgSO4. The solvent is removed under reduced pressure and residue purified by flash chromatography using EtOAc as eluent to afford 200 mg (59%) of the title compound as a yellow gum. HPLC (max plot) 98%; Rt 5.46 min. LC/MS: (ES+): 775.7, (ES−): 773.9.
Reaction SMILES: [NH3:1].CO[C:4](=[O:38])[CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:11][CH:10]=1>CO>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:4](=[O:38])[NH2:1])=[CH:10][CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 63 %

Procedure:
Ammonia (7 M in methanol, 20 mL) was added to a solution of N-Boc methyl ester 100 (718 mg, 1.40 mmol) in methanol (5 mL) and the mixture was stirred at room temperature in a sealed tube for 40 h. The mixture was concentrated by rotary evaporation and purified by flash silica gel column chromatography using methanol/dichloromethane (1:30, 1:20, v/v) to give the desired amide 110 as a white solid (436 mg, 63% yield). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.48-1.68 (m, 4H), 2.09-2.32 (m, 2H), 2.48-2.61 (m, 2H), 3.08-3.25 (m, 2H), 3.97-4.20 (m, 2H), 4.30-4.45 (m, 1H), 4.75 (br s, 1H), 5.09 (s, 2H), 5.48-5.58 (m, 1H), 5.62 (br s, 1H), 6.38 (br s, 1H), 6.75-6.85 (m, 2H), 6.99-7.10 (m, 2H), 7.28-7.40 (m, 5H). m/z (ESI) 500 [C27H37N3O6+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(F)cc1C
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-N-methoxy-N-methylpropanamide (example 141, step 3) to give the title compound as a light yellow oil, MS (ESI+): m/z=430.06 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:8][CH3:9])=[N:5][S:6][CH:7]=1)#[N:2].S(=O)(=O)(O)[OH:11]>>[C:1]([C:3]1[C:4]([O:8][CH3:9])=[N:5][S:6][CH:7]=1)(=[O:11])[NH2:2]
Reactant: COc1nscc1C#N
Reactant: O=S(=O)(O)O
Product: COc1nscc1C(N)=O

Procedure:
A solution of 2.8 g. (0.02 mole) of 4-cyano-3-methoxyisothiazole prepared as in Example 18 in 30 ml. of 75% sulfuric acid was heated at 70° C. for 0.5 hour. The solution was then cooled and poured into ice to give after filtration and drying 0.95 g. of 4-carbamoyl-3-methoxyisothiazole, m.p. 165°-168° C. By continuous ether extraction of the aqueous filtrate an addition 1.13 g. of 4-carbamoyl-3-methoxyisothiazole was obtained to give a total yield of 2.08 g. (66%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[NH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O.[OH-].[Na+]>[Br-:1].[CH2:2]1[N+:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCCCBr
Reactant: C1CCCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C1CCC[N+]2(CC1)CCCCC2
Product: [Br-]
Temperature: 25 °C

Procedure:
A slight excess of 1,5-dibromopentane was added dropwise to a solution of azepane and sodium hydroxide in water and stirred at reflux for several hours. The solution was then cooled to room temperature and diluted with aqueous sodium hydroxide. The reaction mixture was then extracted with chloroform, washed with water several times and evaporated to dryness to yield the white solid 6-azonia-spiro[5,6]dodecane bromide with a melting point of 260° C. 1H-NMR (300 MHz, D2O) δ 1.50 (m, 6H, CH2), 1.75 (m, 8H, CH2), 3.20 (t, 4H, N—CH2), 3.30 (t, 4H, N—CH2).