Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][Cl:9].C([O-])([O-])=[O:12].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][Cl:9]
Reactant: ClCc1c(Cl)cncc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 3,5-dichloro-4-chloromethyl-pyridine (0.55 g, 2.8 mmol) in DCM (10 mL) 3-methyl-benzenecarboperoxoic acid (2.9 g, 16.8 mmol) was added. After stirring for 50 h at room temperature, saturated aqueous Na2CO3 solution (20 mL) and DCM (40 mL) were added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (elution with EA/hexane 1:2) to give the title compound. MS (m/z): 214.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(O)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-(3-fluorophenyl)ethanol (0.7 ml; 5.6 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (224 mg; 5.6 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (780 mg, 5.6 mmol) in dimethylformamide was chilled to 0° C., and activated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford g of solid (yield) of 2-fluoro-6-[1-(3-fluorophenyl)-ethoxy]-benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=C3C(=CC=2)[NH:46][C:45](=[O:53])[CH2:44][O:43]3)OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]5[C:23](=[CH:24][CH:25]=4)[NH:46][C:45](=[O:53])[CH2:44][O:43]5)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1COc2c(ccc3c(=O)c(I)c(-c4ccccc4)oc23)N1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c5c(ccc4c3=O)NC(=O)CO5)cc2)CCC1
Yield: 44 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-phenyl-1H-4,5-dioxa-1-aza-phenanthrene-2,8-dione was reacted to give the title compound as a yellow oil (92 mg, 44%). LCMS (Method H): RT=−4.71 min, [M+H]+=539.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[C:6]([CH:13]=1)[O:7][CH:8]([CH3:12])[C:9](O)=[O:10].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:9](=[O:10])[CH:8]([O:7][C:6]1[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH:14][C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: CN(C)CCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCN(C)C)c2c1C

Procedure:
Prepared analogously to example 32.3 from 2-(5-fluoro-2-(6-(methoxycarbonyl)-5-methylthieno[2,3-d]pyrimidin-4-ylamino)phenoxy)propanoic acid (200 mg) and 2-dimethylaminoethylamine (70 μl)
Reaction SMILES: N1[C:2](=[O:10])N=C2C=CC=CC=12.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=1[NH2:23])(=[O:13])[CH3:12]>C(#N)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([C:11](=[O:13])[CH3:12])[C:2](=[O:10])[NH:23][C:16]=2[CH:17]=1)#[N:22]
Reactant: CC(=O)Nc1ccc(C#N)cc1N
Reactant: O=C1N=c2ccccc2=N1
Solvent: CC#N
Product: CC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Temperature: 77 °C

Procedure:
6—Cyano-3N-acetylbenzimidazolone (1.47 mmol, 0.29 g) which was synthesized similarly to its benzimidazolone analog except that 1N-acetyl-2-amino-4-cyanoaniline was used as starting material and 3-(4-biphenyl)-1,2-propen-3-one (1.37 mmol, 0.29 g) were combined in 15 mL of acetonitrile to form a suspension. The reaction mixture was warmed to 77° C. and heated for 24 h. The reaction mixture was concentrated and the resulting residue was purified by standard chromatographic technique to give crude 1-(4-biphenylcarbonyl)ethyl-6-cyano- 3N-acetylbenzimidazolinone. The crude material was subjected to Pinner conditions followed by reaction with ammonium carbonate to give the title compound 1-(4- biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone. LRMS: m/z 385 (M+H,100). HRMS: calcd for C23H21N4O2, 385.166451; found, 385.167149.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]2[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[CH:8]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]3[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=2)[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccc(C(F)(F)F)cc4)c(C(N)=O)s3)c2)CC1
Reaction time: 15 h
Yield: 59.5 %

Procedure:
A mixture of 0.1041 g (0.239 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.47b), 5 mL of dichloromethane, 0.0781 g (0.772 mmole) of 1-methyl piperazine and 0.2665 (1.195 mmole) of sodium triacetoxyborohydride was stirred for 15 hours. The mixture was treated with 1 mL of saturated ammonium chloride, followed by 10 mL of saturated sodium bicarbonate and 5 mL of dichloromethane. The mixture was stirred for 45 minutes. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 1:99-20:80) to give 0.074 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(4-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide (VI.47c) as a light orange solid.
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])Br.COC(=O)C(C1C=CC(Cl)=CC=1C(OC)=O)Br.[F:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([SH:43])[CH:36]=1.OC1C=CC=CC=1C#N>>[OH:13][C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2[S:43][C:37]3[CH:36]=[C:35]([F:34])[CH:42]=[CH:41][C:38]=3[C:39]=2[N:40]=1
Reactant: COC(=O)c1ccccc1C(Br)C(=O)OC
Reactant: N#Cc1ccc(F)cc1S
Agent: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Agent: N#Cc1ccccc1O
Product: Oc1nc2c3ccc(F)cc3sc2c2ccccc12

Procedure:
The procedure was similar to step S19B, while the starting material was 29A in stead of 19A, and used 4-fluoro-2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CN([P+]([O:54][N:55]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C)C=O.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[NH:55][OH:54])=[CH:25][CH:26]=2)=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Acid compound 4 (1.1 g, 2.24 mmol) was dissolved in N,N-dimethylformamide (10 mL) and stirred under an atmosphere of argon. N-Methylmorpholine (1.0 mL, 8.96 mmol) was added, the reaction mixture was cooled to 0° C. and BOP reagent (1.09 g, 2.46 mmol) was added. After 20 min, hydroxylamine hydrochloride (0.31 g, 4.48 mmol) was added and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and residual material was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (1×30 mL). The organic layer was dried and concentrated to yield the crude material. Flash chromatography on SiO2 gel using hexanes-ethyl acetate (1:1) mixture containing 1% acetic acid furnished the desired hydroxamic acid compound 5 (0.5 g, 44%). 1H NMR (DMSO-d6): 11.20 (br, 1H), 9.00 (br, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.28-7.38 (m, 7H), 6.98 (overlapped d, J=8.4 Hz, 4H), 5.12 (s, 2H), 4.21-4.27 (m, 1H), 3.03 (dd, J=13.6 and 5.6 Hz, 1H), 2.89 (dd, J=10.0 and 14.0 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:7]
Reactant: COc1ccc(CN2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)OC[C@@H]2[C@@H](C)O)cc1
Yield: 79 %

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (5.90 g, 19.2 mmol) in CH2Cl2 (40 mL) was treated with TFA (40 mL) at room temperature for min. The reaction mixture was concentrated in vacuo, then diluted with CH2Cl2 (˜50 mL), and again concentrated. This procedure was repeated three times to remove TFA. Flash column chromatography (EtOAc/Heptane 30-100%) gave 3.81 g (R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one. 1H NMR (400 MHz, MeOD) δ 7.31-7.21 (m, 2H), 7.00-6.87 (m, 2H), 4.67 (d, J=15.0 Hz, 1H), 4.34-4.18 (m, 3H), 3.95 (q, J=6.2 Hz, 1H), 3.80 (s, 3H), 3.68 (dt, J=8.7, 5.5 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H). MS m/z 252.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.CO.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.1 %

Procedure:
Process B: (3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (3.00 g), sodium azide (2.32 g), triphenylphosphine (3.43 g) and N,N-dimethylformamide (60 mL) were mixed together. While this mixture was chilled in an ice water bath, carbon tetrabromide (4.34 g) in dichloromethane (14 mL) was added dropwise. The reaction mixture was stirred at room temperature for 25 hours and then at 60° C. for 2 hours. Subsequently, methanol (5 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate:hexane=2:1) to give (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a pale brown syrup (2.94 g).
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][C:7]1[C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:5])=[O:4].C[O-].[Na+].Cl>CO.O>[CH3:1][N:2]1[S:3](=[O:5])(=[O:4])[NH:6][C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]1=[O:15]
Reactant: CNS(=O)(=O)Nc1ncccc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1C(=O)c2cccnc2NS1(=O)=O

Procedure:
Methyl 2-(((methylamino)sulfonyl)amino)-3-pyridine carboxylate (11.0 grams; 0.045 mole) was dissolved in 150 ml of methanol and sodium methoxide (7.3 grams; 0.135 mole) added thereto. The resulting reaction mixture was heated at reflux temperatures for a period of about four hours. After cooling the reaction mixture, the solvent was removed in vacuo and the residue thus obtained suspended in 30 ml of water and the resulting suspension acidified to a pH of about 1.0 with concentrated hydrochloric acid. The reaction mixture was filtered and the precipitate thus obtained was washed with several portions of water and dried in vacuo. As a result of such operations, the desired title compound was obtained as a white powder having a melting point of 290° C.-292° C.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][C:35]1[NH:36][CH2:37][CH2:38][N:39]=1>>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][C:35]3[NH:39][CH2:38][CH2:37][N:36]=3)=[CH:14][N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCC1=NCCN1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCC2=NCCN2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-chloromethyl-2-imidazoline.
Reaction SMILES: [S].N.[SH2:3].[CH2:4](Cl)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:4]([S:3][S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCl
Reactant: S
Agent: N
Agent: [S]
Solvent: CO
Product: CCCCCCSSCCCCCC
Reaction time: 2 h
Yield: 83.5 %

Procedure:
1.5 mole sulfur, 6 moles of ammonia and 1.5 mole of hydrogen sulfide were charged into a 3 liter stainless steel autoclave and heated to 70° C. as 3 moles of n-hexyl chloride and 250 ml. of methanol were pumped into the vessel. After 2 hours at 70° C., the mixture was filtered free of ammonium chloride and the filtrate was distilled to give an 83.5 percent yield of di-n-hexyl disulfide, boiling point 120° - 122° C. and 1 mm. n D25 1.4864, d 425 0.9145, RD 0.341, calculated RD 0.315.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[I:39]I>O1CCCC1.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[C:33]([I:39])[CH:34]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of butyllithium (2.5 M in hexanes) (6.31 ml, 15.79 mmol) in tetrahydrofuran (125 ml) at 0° C., was added 2,2,6,6-tetramethylpiperidine (3.808 ml, 22.56 mmol). The reaction mixture was then stirred at room temperature for 1 h. The mixture was cooled to −78° C. and then a solution of 4-(6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D9) (2.5 g, 7.52 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred for 1 h. at −78° C. before adding a solution of iodine (2.29 g, 9.024 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at −78° C. for 1 h. and then diluted with a 10% solution of acetic acid in tetrahydrofuran. The mixture was then allowed to reach room temperature and then the solvent was evaporated in vacuo. The residue was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was precipitated from diethyl ether to yield D10 (2.81 g, 82%) as a light yellow solid. C14H18F3IN4O2 requires 458; Found 459 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[NH2:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([NH:29][C:28]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1ccc(-c2cc(Nc3cc(OC)c(OC)c(OC)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150.0 mg, 0.459 mmol) and 3,4,5-trimethoxy aniline were reacted as starting materials at 140° C. for 5 hours and post treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (155.0 mg, 71.3%). Melting point: 125.4-126.3° C. (chloroform-hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:27]([OH:29])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][NH2:40])([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:27]([NH:40][CH2:39][CH:38]([OH:41])[CH2:37][NH:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:42])=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.20 g (0.50 mmol) of N2,N5-bis[(benzyloxy)carbonyl]-L-ornithine and 0.124 g (0.65 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.124 g (0.65 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:8][C:5]1[O:6][CH2:7][C:3]([CH2:2][OH:1])([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[N:4]=1
Reactant: BrCCCOc1ccccc1
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=NC(CO)(CCc2ccc(OCCCOc3ccccc3)cc2)CO1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and (3-bromo-propoxy)-benzene (273 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hexane 9:1) affords (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.135 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-2-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-propane-1,3-diol hydro-chloride as a colorless powder. ESI+ MS: m/z=370.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinic acid (D98) (150 mg, 0.5 mmol), methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (114 mg, 0.5 mmol) and N,N-Diisopropylethylamine (194 mg, 1.5 mmol) in dimethylformamide (10 ml) was stirred 1 h at room temperature, then benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (312 mg, 0.6 mmol) was added. The mixture was stirred at room temperature overnight, then poured into ice-water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic solution was washed with brine (40 ml), dried over Na2SO4 and concentrated to obtain a residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate (4:1). Collected fractions after solvent evaporation afforded the title compound (D142) (189 mg) as a yellow solid.