Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(OCC)(=O)C>[NH:15]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@H:2]([C:3]([N:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[O:5])[CH3:1]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
10.32 g of Z-Ala-ONP and 5.0 g of H-Pro-OtBu in 10 ml of ethyl acetate are allowed to stand for one hour at 0°C and 15 hours at room temperature. The mixture is then diluted with 100 ml of ethyl acetate, washed with 50 % saturated potassium carbonate solution and water, dried over sodium sulphate and evaporated. The resulting oil is homogeneous according to a thin layer chromatogram on silica gel (Rf = 0.65 in the system chloroform-methanol (9:1)) and is directly used further.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][N:23]=1.CC[O:32]C(C)=O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:26]([C:25]1[CH:24]=[N:23][C:22]([Cl:21])=[CH:29][CH:28]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl[2-amino-4-(2-thienyl)phenyl]carbamate (E) (600 mg, 2.07 mmol) and 6-chloronicotinyl chloride (380 mg, 2.16 mmol) in 5 mL of pyridine was stirred overnight, poured into EtOAc and washed with saturated NaHCO3, dried (Na2SO4) and concentrated giving the BOC-protected chloronicotinamide (F): 1H NMR (600 MHz, CD3OD): δ 8.95 (d, J=2.3 Hz, 1H), 8.35 (dd, J=8.2 Hz, 2.3 Hz, 1H), 7.85 (br s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.55-7.51 (m, 2H), 7.37-7.35 (m, 2H), 7.07 (dd, J=5.0 Hz, 3.5 Hz, 1H), 4.59 (s, 1H), 1.49 (s, 9H); MS (ESI+): cal'd [M+Na]+ 452.1, obs'd 452.1.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C=O.[C:31](O)(=O)C.[Na]>C1COCC1>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Reactant: CC(=O)O
Agent: C=O
Agent: [Na]
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 314 (0.38 g), 30% aqueous paraformaldehyde (0.8 mL) and acetic acid (60 μL) in THF was added sodium triacetoxyboronhydride (0.42 g). After stirring at room temperature for two hours, the THF was removed by evaporation under reduced pressure. The residue was partitoned between saturated aqueous NaHCO3 and EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography with 10% to 60% MeOH in DCM. The combined pure fractions were evaporated to give a white solid, which was triturated in EtOAc/DCM (2:1) and filtered. The filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted between water and DCM. The organic phase was dried over anhydrous Na2SO4 and evaporated to give Compound 317 (0.31 g). 1H-NMR (400 MHz, CDCl3) δ: 1.27 (s, 9H), 1.90 (br, 2H), 2.47 (s, 3H), 2.79 (d, J=4.8 Hz, 3H), 3.04 (br, 2H), 4.16 (br, 2H), 4.29 (d, J=9.5 Hz, 1H), 4.32 (br, 2H), 5.95 (br, 1H), 7.20-7.23 (dd, J=2.0, 9.6 Hz, 1H), 7.47-7.53 (m, 5H), 7.82 (d, J=9.5 Hz, 1H). LCMS (+ESI) m/z 398.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:64][P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[F:64][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:37][C:27]([C:26]2[C:20]3[NH:19][C:18]([C:12]4[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=4[NH:10][CH2:9][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[N:22][C:21]=3[CH:23]=[CH:24][CH:25]=2)=[O:28])=[CH:32][CH:33]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid 4-fluoro-benzylamide was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid 4-fluoro-benzylamide. LC/MS calcd for C28H23ClFN5O2 (m/e) 515.0, obsd 516 (M+H). 1H NMR (tautomers, DMSO-d6): 13.30-13.51 (m, 1H), 11.11-11.49 (m, 1H), 9.98-10.95 (m, 1H), 9.06-9.36 (m, 1H), 7.68-8.00 (m, 2H), 6.93-7.65 (m, 11H), 6.22 (d, J=7.3 Hz, 1H), 4.47-4.74 (m, 2H), 3.59-3.85 (m, 2H), 3.05 (t, J=6.9 Hz, 2H).
Reaction SMILES: [CH2:1]([Si:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Cl)=[CH:26][CH:25]=1>>[CH2:1]([Si:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: CCC[Si]1(c2ccccc2)CCC(C2CC=C(c3ccc(F)cc3)CC2)CC1
Yield: 82 %

Procedure:
In the same manner as in Example 1, 35.0 g of 4-(4-n-propyl-4-phenyl-4-silacyclohexyl)cyclohexanone were subjected to coupling reaction with 4-fluorophenylmagnesium chloride, followed by dehydration reaction in the presence of an acid catalyst to obtain 35.9 g of 4-(4-n-propyl-4-phenyl-4-silacyclohexyl)-1-(4-fluorophenyl)-1-cyclohexene (yield: 82%). The results of 1H-NMR analysis are shown below. 1H-NMR (CDCl3) δ:0.50-2.55 (23H, m), 5.90-6.14 (1H, m), 6.80-7.65 (9H, ppm
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].C([O:21]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][C:5]([CH:11]=[O:21])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COCCOc1cc(C)c([N+](=O)[O-])cc1Cl
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)c([N+](=O)[O-])cc1Cl
Reaction time: 1 h

Procedure:
1-Chloro-2-(2-methoxyethoxy)-4-methyl-5-nitrobenzene (300 mg; 1.22 mmol) in DMF (3 ml) was treated with tert.butoxy-bis(dimethylamino)methan (1.06 ml; 5.1 mmol) in DMF (13 ml) at 160° C. for 20 min. The reaction mixture was evaporated to dryness and taken up in THF (6 ml). NalO4 (1.6 g; 7.3 mmol) in water (25 ml) was added at room temperature within 0.5 h and after stirring for another 1 h, the reaction mixture was extracted with EtOAc twice. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the intermediate 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde as brown solid (360 mg; quant.). 4-chloro-5-(2-methoxyethoxy)-2-nitrobenzaldehyde (360 mg; 1.22 mmol) and (methoxycarbonylmethylen)triphenylphosphoran (449 mg; 1.34 mmol) were refluxed for 1 h in toluene (20 ml). After cooling the reaction mixture, toluene (100 ml) was added and the resulting crystals filtered off and purified via chromatography (SiO2, TBME/hexanes 1/1) to yield the title compound as a cis-trans mixture (290 mg). Recrystallisation from hot TBME rendered the pure trans isomer (180 mg; 47%) as slightly yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:21][C:22](=[NH:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]4[O:19][N:33]=[C:22]([C:23]5[CH:24]=[C:25]([S:29]([NH2:30])(=[O:31])=[O:32])[CH:26]=[CH:27][CH:28]=5)[N:21]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4ccc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.22) (137 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7](161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (dichloromethane/MeOH) and crystallization (dichloromethane) as an off-white solid (86 mg, 38%). MS (ISN) 451.2 [(M−H)−]; mp 223° C.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (10.85 mmol) cis-4-tert-Butylcyclohexanecarboxylic acid (Example 42A) are dissolved in 50 ml dichloromethane, 1.65 g (13.02 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[S:42]1C=C[CH:44]=[C:43]1CC(O)=O>>[N:1]1([CH2:6][CH2:7][O:8][C:43](=[S:42])[CH3:44])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCn1ccnc1
Reactant: O=C(O)Cc1cccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=S)OCCn1ccnc1

Procedure:
2-(1-Imidazolyl)ethanethiolacetate can be prepared by a method similar to that described in Example 11 for the preparation of the starting material, but starting from 2-(1-imidazolyl)ethanol (15 g), triphenylphosphine (70.2 g), diisopropyl azodicarboxylate (55.8 cc) and thiolacetic acid (21 cc). After purification by "flash" chromatography [eluent: methylene chloride (1500 c), followed by ethyl acetate-methanol (80-20 by volume)], 100-cc fractions being collected, and concentrating fractions 21 to 35 to dryness under reduced pressure (2.7 kPa) at 30° C., 2-(1-imidazolyl)ethylthioacetate (21.14 g) is obtained in the form of an orange-yellow oil which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 51.5 %

Procedure:
To a solution of 2-methyl-1H-indole-3-carboxylic acid (3.3 g, 18.85 mmol), 1-hydroxybenzotriozole (4.69 g, 37.7 mmol, 2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.24 g, 37.7 mmol, 2 eq), triethylamine (20.0 mL) in dichloromethane (100 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (5.77 g, 37.7 mmol, 2 eq). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:2) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (3.00 g, 9.7 mmol, 51%). LRMS (M+H+) m/z: calcd 309.36. found 310. HPLC Purity (214 nm): >95%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1H), 11.43 (s, 1H) 7.74 (d, J=5.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.04 (t, J=6 Hz, 3H), 5.89 (s, 1H), 4.32 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1.[Na].[PH2:13]([O-:15])=[O:14].[CH:16]([NH3+:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:16]([NH:29][CH:10]([P:13]([OH:15])[OH:14])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH3+]C(c1ccccc1)c1ccccc1
Reactant: O=[PH2][O-]
Reactant: COc1ccc(CC=O)cc1
Agent: [Na]
Product: COc1ccc(CC(NC(c2ccccc2)c2ccccc2)P(O)O)cc1

Procedure:
10 parts of freshly distilled p-methoxyphenylacetaldehyde in 20 parts of sodium-dried dioxan was added to a suspension of 17 parts of benzhydrylammonium hypophosphite in 100 parts of sodium-dried dioxan under reflux and under nitrogen as in Example 17 above. 70 Parts dioxan/water was removed. 125 Parts of alcohol was added and DL-1-benzhydrylamino-2-(4-methoxyphenyl)-ethanephosphonous acid, melting point 199°-202°, was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([N:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:1]([O:3][C:4](=[O:31])[C:5]([N:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: C#CCCCCCC
Reactant: CCCCCCC#Cc1ccc(CN(Cc2ccc(Br)cc2)C(=O)C(=O)OCC)cc1
Product: CCCCCCC#Cc1ccc(CN(Cc2ccc(C#CCCCCCC)cc2)C(=O)C(=O)OCC)cc1
Yield: 32 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl[(4-bromobenzyl)(4-oct-1-ynylbenzyl)amino](oxo)acetate and 1-octyne gave the title compound as a pale yellow oil (32%). 1H NMR (CDCl3, 300 MHz) δ 7.38 (m, 4H), 7.16 (d, 2H, J=8.3 Hz), 7.12 (d, 2H, J=7.9 Hz), 4.45 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), 4.28 (s, 2H), 2.42 (t, 4H, J=7.1 Hz), 1.62 (m, 4H), 1.47 (m, 4H), 1.33 (m, 11H), 0.92 (t, 6H, J=6.8 Hz). M+(LC/MS(ESI)): 514.0. HPLC (Condition A), Rt: 6.54 min (HPLC purity: 99.3%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([NH:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72])=[O:7]
Reactant: CCN(c1cc(Br)c(F)c(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(c1cc(Br)c(F)c(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid (200 mg, 0.56 mmol) in N,N-Dimethylformamide (2 ml) at room temperature and under nitrogen was added PyBOP (346.72 mg, 0.67 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (145 μl, 0.83 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 104 mg, 0.61 mmol). After stirring for 1 hour at room temperature no starting material was observed by LCMS. EtOAc (20 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3 (aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 97:3 DCM:MeOH) to give 112 mg (41%) of 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide as a pale yellow solid. LC-MS 97%, 1.85 min (3 minute LC-MS method), m/z=494.0/496.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.66 (s, 1H), 7.23 (d, J=6.5 Hz, 1H), 5.95 (s, 1H), 4.65-4.43 (m, 2H), 3.93 (d, J=11.0 Hz, 2H), 3.38-3.22 (m, 2H), 2.97 (q, J=7.0 Hz, 2H), 2.91-2.79 (m, 1H), 2.37 (s, 3H), 2.24-2.11 (m, 6H), 1.72-1.53 (m, 4H), 0.83 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:24])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)CC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](CC2CCCCC2)NC(=O)C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.31 g (0.94 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine and 0.26 mL (1.87 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.15 g (1.03 mmol) of cyclohexanecarboxylic acid chloride in 4 mL of dichloromethane. The reaction mixture was allowed to stir under nitrogen at 0° C. for one hour, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and then converted to the dihydrochloride salt of the title compound with ethanolic HCl to yield 0.41 g (85%) as a beige solid; mp=121–131° C.; MS (+) ESI m/z=442 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].[N:25]1([C:35](N2C=C[N+](C)=C2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:35]([N:25]2[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]2)=[O:36])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)cc1OC
Yield: 21.2 %

Procedure:
The title compound (50 mg, 21% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[H-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[C:28]([Si:25]([O:24][CH2:23][CH2:22][CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=1[F:18])([CH3:27])[CH3:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (4.0 g, 12.5 mmol) was dissolved in 40 mL dry DMF. (2-Bromo-ethoxy)-tert-butyl-dimethylsilane (4.1 g, 17.1 mmol) and NaH (2.28 g, 95.0 mmol) were added respectively. The solution was stirred at room temperature overnight. 200 mL of water and 200 mL of EtOAc were added. The aqueous layer washed with 100 mL of EtOAc. The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified using column chromatography (hex./EtOAc 100/0 to 90/10 in 45 min, 1.7 g, 28%). 1H NMR (CDCl3 400 MHz) δ 7.65 (m, 2H), 7.46 (m, 2H), 7.14 (m, 1H), 6.84 (m, 0.5H), 6.73 (m, 0.5H), 4.87 (m, 1H), 4.79 (m, 1H), 4.37 (m, 1H), 2.55 (m, 2H), 2.04 (s, 9H), −0.13 (d, J=22.7 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10]([O:14][C:15]([NH:17][C@H:18]([C:23](O)=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:11][C:10]([O:14][C:15](=[O:16])[NH:17][CH:18]([C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:24])[CH:19]([CH3:20])[CH2:21][CH3:22])([CH3:13])[CH3:12]
Reactant: NCCc1ccccn1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCCc1ccccn1

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 2-(2-amino-ethyl)pyridine, 2.163 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.15 g of BOP, 10.52 g of Hunig's base, and 15 ml of methylene chloride to give 2.5 g of the product as a white/yellow powder.