Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:27]>CN(C=O)C.O>[CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[N:13]([CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[O:27])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Reactant: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(B) (100 mg, 0.354 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 15 mg, 0.372 mmol). The reaction was stirred at 0° C. for 30 minutes, was cooled to −10° C. and 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 1(B) (107 mg, 0.372 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature for 24 h and was diluted with water. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% EtOAc in hexanes to 100% EtOAc) to provide 861.8 mg of 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.11-7.48 (m, total 3H), 7.36 (m, 3H), 6.79 (dd, 1H), 4.99 (m, 1H), 4.12 (m, 2H), 3.92 (d, 3H), 3.65 (d) and 3.82 (d, total 1H), 3.46 (dd, 1H), 2.83 (m, 1H), 2.20 (d, 1H), 2.03-1.86 (m, 3H), 1.68 (m, 2H), 1.54 (m, 2H) 1.31-1.41 (m, 2H), 1.07 (m, 6H); MS 489.4 (M+1), 487.4 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[C:3]=1[CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]1=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:17]2=[O:27])=[C:4]([F:14])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([N:60]2[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]2)=[O:13])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCCc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCCc2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2F)CC1
Temperature: 80 °C

Procedure:
Add 4-[4-chloro-3-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-2-fluoro-phenyl]-butyric acid (Preparation 80) (200 mg, 0.22 mmol), EDAC (63 mg, 0.33 mmol), HOBT (45, mg, 0.33 mmol), triethylamine (0.1 mL, 0.7 mmol) and 1-methylpiperazine (0.1 mL, 0.9 mmol) in THF (5 mL). Heat the mixture at 80° C. for 3 hours. Evaporate solvent and purify the residue by column chromatography to give the title product as white solid: Mass spectrum (ion spray): m/z=478.3 (M+H).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].O[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1>CN(C=O)C.C(Cl)Cl>[Cl:3][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1
Reactant: O=C1C=C2Sc3ccc4nc(CO)ccc4c3CC2=CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C=C2Sc3ccc4nc(CCl)ccc4c3CC2=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 438.2 %

Procedure:
A solution of cyanuric chloride (0.29 g, 0.16 mmol) in DMF (1 mL) was stirred for 0.5 hrs, resulting in a white precipitate. Dichloromethane (30 mL) was added, followed by a solution of 3-hydroxymethylpyridothioxanthone (0.25 g, 1.0 mmol) in DCM (20 mL). The solution was stirred at r.t. overnight, then washed with hydrochloric acid (0.5 M, 30 mL) and water, and then dried over sodium sulfate. The mixture was purified by column chromatography on silica gel with DCM/hexane (2:3) as the eluant, yielding 3-chloromethylpyridothioxanthone (0.22 g, 82%). 1H-NMR (CDCl3): 8.88 (1H, d, J 8.4, H1), 8.61 (1H, d, J 8.1, H8), 7.73-7.64 (3H, m, H2+H5+H6), 7.57-7.52 (1H, m, H7), 4.76 (2H, s)). m/z (ES+): 262 [M+H]+, 284 [M+Na]+, 545 [2M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12](Cl)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[C@H:15]1([NH2:22])[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:21][CH:18]2[CH2:19][CH2:20][CH:15]([NH2:22])[CH2:16][CH2:17]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 50-mL round-bottom flask placed a solution of 10,12-dichloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (500 mg, 2.04 mmol, 1.00 equiv) in anhydrous CH3CN (20 mL) was added trans-cyclohexane-1,4-diamine (280 mg, 2.45 mmol, 1.20 equiv) and potassium carbonate (844 mg, 6.11 mmol, 3.00 equiv) at room temperature. The resulting solution was stirred overnight at 80° C. under nitrogen. The resulting solution was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted (520 mg, crude) of 1-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a white solid which was used directly for next step without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:18][S:19]([O:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:13]=1)(=[O:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Cyclohexylamino)-5-nitropyridin-2-ol (1.35 g, 5.69 mmol) was dissolved in DCM (1150 mL). Methanesulfonyl chloride (0.782 g, 6.83 mmol) and triethylamine (1.152 g, 11.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, acidified with 1 M HCl and extracted with DCM. The organic layers were combined, washed with water, dried over Na2SO4, and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=316.30 [M+H]+.
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-])(=O)[CH2:18][CH2:19]NC(=O)[C@@H](C(CO)(C)C)O.F[C:33](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.COC(OC)(C)C>[CH3:33][O:14][C:1](=[O:15])[CH2:2][CH2:3][NH:4][C:5]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH2:11][O:12][C:18]([CH3:19])([CH3:17])[O:7]1)=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: COC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Reaction time: 8 h

Procedure:
A 5.0 g portion of calcium pantothenate was slurred in 100 ml of acetone:2,2-dimethoxypropane (1:1). Trifluoroacetic acid (3.0 ml) was added until solution was complete and stirring was continued overnight. A 10 g portion of potassium carbonate was added, this mixture stirred vigorously for 10 minutes and then concentrated to a gummy solid. A 100 ml portion of acetonitrile and 10 ml of methyl iodide were added to the solid. This mixture was stirred for 1 day, then poured into water and extracted twice with ethyl acetate. The extracts were combined, dried and concentrated, giving 4.8 g of the desired compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[C:7]([C:9]1[CH:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:17][CH2:16]2)=[N:11][CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (crude, 2.6 mmol assumed) and triethylamine (780 mg, 7.8 mmol) in dichloromethane (10 mL) was added benzyl chloroformate (663 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 2 hours, and diluted with dichloromethane (100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (etroleum ether/ethyl acetate=4:1˜2:1) to give benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 57%) as a yellow solid. MS (ES+) C23H22N4O3 requires: 402, found: 403 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34]O)=[N:27][C:28]=1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[N:27][C:28]=1[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Under an argon atmosphere, to a solution of methyl 3-(3-hydroxyphenyl)propanoate (131 mg), (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (200 mg) and triphenylphosphine (259 mg) in THF (3.0 mL) was added a about 2.2 M solution of diethyl azodicarboxylate in toluene (450 μL), and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (249 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]Br.Cl.[CH2:15]([O:17][NH2:18])[CH3:16]>C(N(C(C)C)C(C)C)C>[ClH:1].[CH2:15]([O:17][NH:18][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:8]=1[Cl:13])[CH3:16]
Reactant: Clc1cc(Cl)c(OCCBr)c(Cl)c1
Reactant: CCON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCONCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 96 h
Yield: 105.9 %

Procedure:
30.4 g (0.1 mole) of 2,4,6-trichlorophenoxyethyl bromide were added to a suspension of 48.5 g (0.5 mole) of O-ethylhydroxylamine hydrochloride in 250 ml of ethyldiisopropylamine, and the mixture was stirred for 4 days at 50° C. and then cooled to 15° C. and filtered under suction. The filtrate was evaporated down under reduced pressure, in the final stage at 60° C. and under 0.1 mbar, the residue was dissolved in 300 ml of ether, and the solution was gassed with hydrogen chloride at +3° C. 17 g of O-ethyl-N-(2,4,6-trichlorophenoxy)ethylhydroxylamine hydrochloride of melting point 173°-175° C. were obtained.
Reaction SMILES: Cl.CO[C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[OH-].[NH4+:20]>>[OH:17][C:14]1[CH:15]=[C:16]2[C:11]([NH:10][CH:9]=[C:8]2[CH2:7][C@@H:5]([C:4]([NH2:20])=[O:18])[NH2:6])=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Agent: Cl
Agent: [OH-]
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12

Procedure:
(S)-5-Hydroxytryptophan methyl ester hydrochloride (0.247 g, 0.91 mmol) was stirred overnight at room temperature in ammonium hydroxide (10 mL). After removal of volatiles under vacuum, the title compound of example 44 was obtained as a dark solid.
Reaction SMILES: [CH2:1]([N:11]=[C:12]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C(Cl)(=O)CCCCCCCCC=C.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH2:1]([NH:11][C:12]([NH:35][O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCN=C=O
Reactant: NOCc1ccccc1
Agent: C=CCCCCCCCCC(=O)Cl
Solvent: ClCCCl
Product: C=CCCCCCCCCNC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 9-decenyl isocyanate, prepared as in Example 18 above from 10.8 ml of 10-undecenoyl chloride in 1,2-dichloroethane (150 ml) at room temperature was added benzyloxyamine (7.2 g). After 20 minutes, the mixture was evaporated, hexane (50 ml) was added, and the mixture cooled to 0° C. The resulting solids were collected by filtration, to provide N-(9-decenyl)-N'-benzyloxyurea as a white solid (7.14 g, mp 53°-55° C.). To a stirred slurry of this urea (3.50 g, 11.65 mmol) in DMF (35 ml) at room temperature under nitrogen was added sodium hydride (490 mg of a 60% dispersion in oil). After one hour, 1,3-dibromopropane (1.45 ml) was added, and the reaction was stirred for two hours. The mixture was poured into 1% aqueous HCl (200 ml), and extracted twice with ether. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave 3-decyl-1-benzyloxy-3,4,5,6-tetrahydro-lH-pyrimidin-2-one as a colorless oil (1.92 g, 48% yield). Hydrogenolysis as in Example 2 above provided the title compound as a light magenta solid, after recrystallization from carbon tetrachloride, mp 45°-46° C.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([S:4][CH:5]([CH2:6][C:7]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:8])[CH:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:16])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Reactant: NCC(N)=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)NCC(N)=O)SC(C)=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]-amino]carbonyl]heptanoic acid (E5, Isomer A; 226 mg, 0.5 mmol), N-ethyl-N1 -dimethylaminopropylcarbodiimide hydrochloride (116 mg, 0.6 mmol), 1-hydroxybenzotriazole (90 mg, 0.58 mmol), glycinamide hydrochloride (64 mg, 0.58 mmol) and diisopropylethylamine (0.2 ml, 1.14 mmol) in dichloromethane was stirred at 5° C. for 2 h then at room temperature overnight. The mixture was cooled in ice and the solid was collected by filtration and washed well with dichloromethane. The solid was triturated with 1 M citric acid, then filtered, washed with water and dried. Recrystallisation from methanol/ ether gave the title compound as a single isomer (Isomer A), 75 mg (30%) mp 218°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15]([CH2:25]/[C:26](/[CH3:35])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:34])=[CH:31]/[CH2:32]Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:34]/[C:30](/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:35])/[CH2:25][CH2:15]/[CH:16]=[C:17](\[CH3:18])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:31]\[CH2:32][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: O=c1ccc2cc(O)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (474 mg, 2.92 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (117 mg of 60% mineral oil suspension, 2.93 mmol) was added and the solution was stirred at 0° C. for 30 minutes. The crude geranylgeranyl bromide (302.85 mg) from the previous step was dissolved in anhydrous DMF, cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired compound was isolated via preparative thin layer chromatography using a 7:3 Hexanes:Ethyl acetate solvent system. The purified product was characterized by 1H-NMR spectroscopy. 1H-NMR (300 MHz, CD3COCD3): ∂ 1.54-1.75 (15H), 1.93 (m, 12H), 4.65 (2H), 5.09 (3H), 5.53 (1H), 6.40 (1H), 7.11 (3H), 7.81 (1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH:10]C(=O)C)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[K+].O>C(O)C>[NH2:10][CH2:9][CH2:8][N:3]1[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]1[CH3:1]
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1CCN

Procedure:
251.1 g (1.39 mol) of 2,5-dimethyl-1-(2-acetylaminoethyl)-pyrrole, prepared as in Example 5, and 390.8 g (6.97 mol) of potassium hydroxide are heated reflux in 2.8 l of ethanol and 180 ml of water under an atmosphere of nitrogen for 4 h. After the mixture has been concentrated, the aqueous phase is extracted with methylene chloride, and the extract is fractionally distilled. Yield: 150.2 g (78% of theory), Boiling point: 70° C./0.267 mbar
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:37]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([C:18]1[N:19]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:22]=1[Br:37])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCCC[C@@H]1OCc1ccccc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCCC[C@@H]1OCc1ccccc1)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Yield: 86.1 %

Procedure:
A solution of N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide (Table entry 276) (198 mg, 0.380 mmol) and N-bromosuccinimide (88 mg, 0.49 mmol) in dimethylformamide (5 mL) was stirred at 75° C. for 3 days. The solution was purified by preparative HPLC to give N-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-bromo-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide as a white solid (196 mg, 86%). LC-MS m/z 598.1 (MH+), retention time 3.72 min (method 2).
Reaction SMILES: [F:1][C:2]1[C:11](I)=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:39][C:40]1([CH3:47])[C:44]([CH3:46])([CH3:45])[O:43][BH:42][O:41]1>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1>[F:1][C:2]1[C:11]([B:42]2[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:47])([CH3:39])[O:41]2)=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C)c(I)c1F
Reactant: CC1(C)OBOC1(C)C
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 100 ml 3-neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen outlet was placed methyl 2-fluoro-3-iodo-4-methylbenzoate (2.0 g, 6.80 mmol), 10.0 ml of anhydrous 1,4-dioxane, diacetoxypalladium (0.076 g, 0.340 mmol) and [1,1′-biphenyl]-2-yldicyclohexylphosphine (0.477 g, 1.360 mmol) under nitrogen. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.96 ml, 20.40 mmol) was added drop wise via syringe. The reaction mixture was heated at 60° C. for 2 hours and stirred at room temperature overnight. LCMS showed almost 100% conversion. The dioxane was removed and the residue was purified on 80 g ISCO silica column using ethyl acetate/hexane gradient and then switched to methanol/DCM gradient to give 1.25 g (62.5%) of IXS-5-48-1, 1.25 g (62.5%). 1H NMR (DMSO-d6, 400 MHz) δ 7.81 (t, 1H), 7.16 (d, 1H), 3.83 (s, 3H), 2.42 (s, 3H), 1.33 (s, 12H), and MS: [MH+]=295).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To a solution of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.109 g 0.25 mmol) in chloroform (10 ml) was added diisopropylethylamine (Aldrich) (100 μl), 4-dimethylaminopyridine (0.02 g 0.16 mmol) and valeryl chloride (Aldrich) (0.072 g 0.6 mmol) and the reaction was stirred at room temperature for 20 hr. It was washed with M Na2CO3 (5 ml), water (5 ml) and dried (MgSO4). Removal of solvent gave a solid which was purified by SPE chromatography. Elution with cyclohexane:ethyl acetate (2:1) gave the title compound as a white solid (0.075 g 58%).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:19])[N:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C)nn1C
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(C)nn2C)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 3-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole to yield the final compound as a yellow solid, MS (ISP): m/e=343.1 (M+H+).