Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NCCC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2)nc1
Reaction time: 18 h
Yield: 52.2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (0.61 g, 2.54 mmol) with 2-Cyclopentyl-ethylamine (0.38 g, 3.3 mmol), 2 g of 3 Å molecular sieves, and 10 mL of methanol. Stir for 18 h under nitrogen. Add sodium borohydride (0.5 g, 13.2 mmol), and stir for 24 h. Filter through Celite, remove the solvent in vacuo. Partition the residue between water (50 mL) and ethyl acetate (100 mL). Dry the organic phase (sodium sulfate), filter, and concentrate in vacuo. Adsorb on silica, and purify on an ISCO® 100 g system (eluting with 95:5:0.5 to 90:10:1 chloroform/ethanol/ammonium hydroxide) to afford 0.45 g of product. HPLC retention time: 5.93 min (98.7% purity), ESMS (M+): 340.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:17]=[CH2:18])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:17]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2)=[CH2:18]
Reactant: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: C=Cc1cccc2c1CNC2
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2-benzyl-4-vinylisoindoline (58 mmol) in DCE (150 mL) was placed in a 1 L round bottom flask under nitrogen. To this was attached an addition funnel containing a solution of 1-chloroethyl chloroformate (7.51 mL, 69.6 mmol) in DCE. The reaction flask was cooled in an ice bath and the contents of the addition funnel were added dropwise over 20 min keeping the internal reaction temperature<5° C. After the addition was complete the reaction flask was allowed to warm to RT then heated to reflux for 45 min. The contents of the reaction flask were cooled to RT then the solvent removed by evaporation. Methanol (200 mL) was added and the contents of the reaction flask were heated to reflux for 30 min. The reaction flask was cooled and the solvent removed by evaporation. Water (200 mL) was added and the resulting mixture washed with EtOAc (2×250 mL). The aqueous layer was made basic with 2N sodium hydroxide then extracted with DCM (4×250 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and the filtrate evaporated. The remaining residue was subjected to flash column chromatography eluting with DCM/MeOH/ammonium hydroxide 97/3/0.3 to 95/5/0.5. Evaporation of fractions gave the title compound as a brown oil, 6.00 g (41.4 mmol, 71% yield for two steps). LRMS (ESI) m/z 146 [(M+H)+; calcd for C10H12N: 146].
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][C:18]1[C:19]([I:33])=[C:20]([CH2:26][CH:27]([CH2:31][CH3:32])[C:28]([OH:30])=[O:29])[C:21]([I:25])=[CH:22][C:23]=1[I:24])=[O:16]>CC#N>[C:28]([CH:27]([CH2:31][CH3:32])[CH2:26][C:20]1[C:19]([I:33])=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:23]([I:24])=[CH:22][C:21]=1[I:25])([OH:30])=[O:29]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCl)c1I)C(=O)O
Reactant: C1CNCCNCCNCCN1
Solvent: CC#N
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Yield: 7.4 %

Procedure:
According to the procedure described in Example 3, 105.8 g of 1,4,7,10-tetraazacyclododecane (0.62 mol) in 600 ml of CH3CN are added to a suspension of 40 g of 3-[(2-chloro-1-oxoethyl)amino]-α-ethyl-2,4,6-triiodobenzenepropanoic acid (prepared as described in Example 1) (0.62 mol) in 500 ml of CH3CN. 35.8 g of N-[3-(2-carboxybutyl)-2,4,6-triiodophenyl]-1,4,7,10-tetraazacyclododecane-1-acetamide (0.046 mol) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:17][CH2:16]1)=[O:10])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]2=[O:37])[CH2:19][CH2:20]1)=[O:10]
Reactant: O=C(OCc1ccccc1)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
To a solution of 300 mg (0.56 mmol) of 3-[1-(3-benzyloxycarbonylbenzyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 20 mL of methanol was added 8 mg (0.06 mmol) of potassium carbonate and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer separated was washed with brine, dried on sodium sulfate and concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 179 mg (0.39 mmol) of the title compound.
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.O>CN(C=O)C>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)=[O:40])[CH2:9][CH2:10]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(C(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
17α-Hydroxy-21-(1-piperazinyl)pregna-4,9(11)-diene-3,20-dione (EXAMPLE 6A, 5.00 g) is treated in DMF (20 ml) with m-chlorophenylisocyanate (1.84 g) for 3 days. The mixture is poured into water (200 ml). After 1 hr, the liquid is decanted. The solid is dissolved in methylene chloride and is extracted with aqueous sodium bicarbonate The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (3% methanol in methylene chloride to 4%) to give the title compound which is crystallized from hot ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[C:5]([O:22][CH3:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH3:32])[CH:26]=1>CN(C)C=O>[ClH:1].[CH3:23][O:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([F:24])=[CH:26][C:27]=1[CH3:32])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: COc1cccc2c(N3CCc4ccccc4C3)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 55 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 3.26 g of the compound (10 mM) prepared in Example 4 and 15 ml of dimethyl-formamide, 1.7 ml of 4-fluoro-2-methylaniline(20 mM) was added, 2.5 g of the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[CH2:8][C:4]=2[CH:3]=1.[C:17]([O-])(=O)[C:18]([O-])=O>>[OH:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][CH:7]([CH2:9][N:10]([CH2:14][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13])[CH2:8][C:4]=2[CH:3]=1
Reactant: CCCN(C)CC1Cc2cc(O)ccc2O1
Reactant: O=C([O-])C(=O)[O-]
Product: CCCN(CCC)CC1Cc2cc(O)ccc2O1

Procedure:
(+) and (-)-5-hydroxy-2,3-dihydro-N-methyl-N-propyl-3-benzofuranmethylamine, oxalate. M.P. 170°-171° C. (Lu 25-020) and (Lu 25-021).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][C:13]=1[CH2:22][O:23][CH3:24])[CH3:5]>C1COCC1.O>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]=1[CH2:22][O:23][CH3:24])[CH3:5]
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
Lithium hydroxide monohydrate (5.31 g, 127 mmol) was added portion-wise into a solution of methyl 2′-ethyl-2-(methoxymethyl)-1,1′-biphenyl-4-carboxylate (12.0 g, 42.2 mmol) in THF (150 mL) and water (30 mL). The resulting mixture was stirred at RT for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. The organic layers were washed with water and brine, combined and dried (Na2SO4). The solvents were removed under reduced pressure to afford the title compound as a white solid (9.0 g, 80%). HPLC (Method A), Rt 4.2 min (purity: 96.7%). UPLC/MS, M−(ESI): 269.2. 1H NMR (DMSO-d6, 400 MHz) δ 12.9 (1H, bs), 8.08 (1H, s), 7.89 (1H, d), 7.35 (2H, m), 7.23 (2H, m), 7.04 (1H, d), 4.09 (2H, m), 3.17 (3H, s), 2.34 (1H, m), 2.22 (1H, m), 0.94 (3H, t).
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=N[CH:10]=[CH:9]2)=[O:7])C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)CCNC[CH2:32]1)=[O:30])[CH3:27]>CC#N>[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH2:10][CH2:9][N:8]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:21][CH2:22]2)=[O:7])[CH2:12][CH2:32]1)=[O:30])[CH3:27]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1(c2ccc(F)cc2)CCNCC1
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc(F)cc2)CCN(C(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Under inert conditions a 100 mL four necked flask with a magnetic stirrer bar was charged with 0.89 g (5.5 mmol) of CDI in 10 mL MeCN. At 0-5° C. a solution of 0.99 g (5.5 mmol) 1-(4-fluorophenyl)piperazine in 10 mL MeCN was added drop wise during 15 min. The light yellow solution was stirred for 15 min at 0-5° C. and 3 h at 20° C. After 90 min an additional 70 mg CDI was added. 1.2 g (4.8 mmol) 4-(4-fluoro-phenyl)-piperidine-4-carboxylic acid ethyl ester (WO2000071517) in 5 ml MeCN was added. The mixture was heated for in total 5 days to reflux. The reaction mixture was concentrated under vacuum. The residue was dissolved in 15 ml N,N-dimethylacetamide and heated twice for 30 min at 200° C. under micro wave irradiations. The dark brown reaction solution was concentrated under high vacuum. The residue was taken up between 100 mL water and 100 mL ethyl acetate and extracted. The aqueous layers were extracted once with 100 mL ethyl acetate and the organic layers were washed once with 100 mL brine, dried over Na2SO4, filtered off, concentrated under vacuum and purified through column chromatography over silica eluting with a gradient formed from i-propanol and heptane. The product containing fractions were evaporated to yield 0.65 g (29%) of the title compound as light yellow viscous oil. MS ISP (m/e): 458.3 [(M+H)+].
Reaction SMILES: Br[C:2]1[C:10]2[NH:9]C=N[C:6]=2[C:5](Br)=[CH:4][C:3]=1[NH2:12].C[Sn](C)(C)C.[CH:18](Cl)(Cl)Cl.C[N:23]([CH:25]=O)[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:2]1[C:3]2[NH:12][CH:25]=[N:23][C:24]=2[C:5]([CH3:4])=[CH:6][C:10]=1[NH2:9]
Reactant: Nc1cc(Br)c2nc[nH]c2c1Br
Reactant: ClC(Cl)Cl
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Product: Cc1cc(N)c(C)c2[nH]cnc12
Temperature: 140 °C
Reaction time: 24 h

Procedure:
A solution of 4,7-dibromo-5-aminobenzimidazole (1.5 g, 5.1 mmol) in 10 ml of DMF was transferred into pressure bottle under Ar2. To the solution was added tetramethyltin (3.6 ml, 20 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg). The resulting reaction mixture was stirred at 140° C. for 24 h and concentrated in vacuo, yielding a dark oil which was subjected to column chromatography (40% EtOAC/CHCl3) to yield 0.34 g (1.5 mmol, 29%) of the desired product as well as 0.75 g of 4,7-dimethyl-5-aminobenzimidazole.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: OC1CCNCC1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCCCN3CCC(O)CC3)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 4-hydroxy-piperidine were converted to yield 1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidin-4-ol as yellowish oil, MS: 464 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:34][C:35]1[C:40]([Pb+3])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:34][C:35]1[C:40]([CH:10]2[C:11](=[O:13])[CH2:12][CH:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH2:8][C:9]2=[O:14])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1
Reactant: O=C1CC(=O)CC(C2CCOCC2)C1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione (196 mg; 1 mmol) and 4-dimethylaminopyridine (610 mg; 5 mmol) is added dry chloroform (4 ml) under an atmosphere of nitrogen, and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml) and a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform. The reaction mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(3,5-dimethylbiphen-4-yl)-5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=O.[NH2:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:17][O:18][C:19](=[O:31])[CH:20]([OH:30])[CH:21]([NH2:29])[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CO.C(Cl)(Cl)Cl>[CH3:17][O:18][C:19](=[O:31])[CH:20]([OH:30])[CH:21]([NH:29][C:14](=[O:16])[CH:9]([NH:8][C:14](=[O:16])[CH:9]([N:8]1[C:19](=[O:18])[C:20]2[C:3](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:1]1=[O:7])[CH2:10][C:11]1[CH:12]=[CH:27][CH:26]=[CH:25][CH:13]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: COC(=O)C(O)C(N)CC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(O)C(CC1CCCCC1)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared from N-phthalyl-Phe (0.028 g, 95 μmol) and TFA-Leu-3-amino-4-cyclohexyl-2-hydroxy-butanoic acid methyl ester (81.7 μmol) following the procedure of Example 1, second paragraph. Column chromatography (SiO2 gel; 2% MeOH/CHCl3) yielded 0.036 g (73% yield) of pure compound with a diastereomeric ratio of 28:1.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](I)=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3].[CH2:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]#[CH:30])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CCOCC>[CH2:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C@H:23]2[CH2:24][CH2:25][C@H:26]([C:29]#[C:30][C:7]3[C:8]([F:10])=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]=3[F:12])[CH2:27][CH2:28]2)[CH2:19][CH2:18]1)[CH2:14][CH:15]=[CH2:16]
Reactant: CCCc1cc(F)c(I)c(F)c1
Reactant: C#C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=C)CC2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#Cc3c(F)cc(CCC)cc3F)CC2)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.65 g of 1-propyl-3,5-difluoro-4-iodobenzene (prepared according to Example 1a), 0.56 g of trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexylacetylene, 0.053 g of tetrakis(triphenylphosphine)palladium (0), 0.009 g of copper(I) iodide and 6 ml of triethylamine was heated to 90° C. for 17 hrs. The reaction mixture was cooled, partioned between water and ether, the organic phase was separated and the aqueous phase was extracted several times with ether. The combined organic phases were dried over magnesium sulphate, filtered and evaporated. chromatography of the residue on silica gel with hexane and two-fold crystallization, firstly from hexane and then from isopropanol, gave 640 mg of 1-{trans-4-[trans-4-(3-butenyl)cyclohexyl]cyclohexylethynyl}-2,6-difluoro-4-propylbenzene, m.p. (C/N) 48.5° C., cl.p. (N/I) 189.8° C.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:20](OC)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>O1CCCC1.C(OCC)(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]2[O:1][N:2]=[C:3]([N:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)[N:4]=2)[CH:22]=1
Reactant: COC(=O)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccnc3)n2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
tert-Butyl 4-(N-hydroxyamidino)-piperazine-1-carboxylate (320 mg) prepared in Example 36 was dissolved in 3 ml of tetrahydrofuran, 36 mg of sodium hydride was added thereto, the mixture was stirred at 60° C. for 15 minutes, a solution of 360 mg of methyl nicotinate in 2 ml of tetrahydrofuran was added thereto and the mixture was heated to reflux for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and a saturated saline solution and dried over sodium sulfate. The residue prepared by evaporation of the solvent was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=1:1) to give 39.7 mg of the title compound as a white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30]P(=O)(OCC)OCC)=[N:27]2)=[CH:22][CH:21]=1.C=O>O1CCCC1>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH2:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc2ccc(Cl)cc2n1)OCC
Reactant: CC(C)NC(C)C
Agent: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2ccc(Cl)cc2n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) in tetrahydrofuran (15.0 ml) at −10° C. under nitrogen was treated dropwise with a 2.5 M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol). After stirring below 0° C. for 30 min the pale yellow solution was cooled to −20° C. and a solution of diethyl 7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) in tetrahydrofuran was added dropwise. The resulting dark green solution was stirred below 0° C. for 1 h, cooled to −10° C. and treated with paraformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15 min after which the cooling bath was removed and the mixture was stirred at 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (3×200 ml), dried (Na2SO4) and the solvent was removed in vacuo to give a dark brown solid. Column chromatography (ethyl acetate-light petroleum (b.p. 40-60° C.), 1:19) provided the title compound (1.80 g, 59%) as pale yellow crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as cream crystals, m.p. 79.7-80° C. (Found: C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C11H8ClN requires C, 69.67; H, 4.25; N, 7.39; Cl, 18.69%); νmax (nujol)/cm−1 1628, 1609; δH (270 MHz) 5.67 (1H, dd, 2′-H, 3J2′,1′=10.89, 2J2′,2″=1.0 Hz); 6.29 (1H, dd, 2″-H, 3J2″,1′=17.7, 2J2″,2′=0.8 Hz); 7.02 (1H, dd, 1′-H, 3J1′,2″=17.5, 3J1′,2′=10.9 Hz); 7.42 (1H, dd, 7-H, Jo=8.8, Jm=2.1 Hz); 7.53 (1H, d, 3-H, Jo=8.9 Hz); 7.66 (1H, d, 5-H, Jo=8.9 Hz); 8.03 (1H, d, 4-H, Jo=8.3 Hz); 8.05 (1H, s, 8-H). δc (67.8 MHz) 118.6 (2′-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0 (4-C); 137.5 (1′-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fall in the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M+), 165.0, 163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).
Reaction SMILES: C(OC(=O)[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[Cl:23])[C:6]([C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:7])C.[Cl-].[Na+].O.CS(C)=O>C(OCC)(=O)C>[Cl:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:7]
Reactant: CCOC(=O)C(C(=O)c1cnc(C)cn1)c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)c2cnc(C)cn2)c(Cl)c1
Yield: 66.9 %

Procedure:
A mixture of 2-(2-chloro-4-methoxy-phenyl)-3-(5-methyl-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (700 mg, 2 mmol), sodium chloride (130 mg), water (55 mg) and DMSO (10 mL) was heated for 5 h to 140° C. Upon cooling, the reaction mixture was taken up in ethyl acetate and washed (water and then brine). The organic layer was dried (Na2SO4), and the solvent was evaporated. Purification of the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20) gave the title compound (370 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 9.13 (1H, s), 8.54 (1H, s), 7.18 (1H, d), 6.97 (1H, d), 6.70 (1H, dd), 4.57 (2H, s), 3.80 (3H, s), 2.68 (3H, s); MS (m/e)=277.0 [MH+].