Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCCCCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.6 %

Procedure:
Under a nitrogen atmosphere, 4-iodobenzoic acid (1a) (10.6 g, 42.9 mmol) was dissolved in anhydrous dichloromethane (140 mL), and several drops of anhydrous N,N-dimethylformamide were added. Thereafter, oxalyl chloride (4.50 mL, 42.4 mmol) was added at 0° C., and the mixture was stirred at room temperature for 10 hr. The solvent was removed, anhydrous pyridine (70 mL) and n-heptanol (7.0 mL, 49.4 mmol) were added, and the mixture was stirred at 70° C. for 5 hr. The reaction solvent was removed, the residue was diluted with ethyl acetate, washed with distilled water and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:19) to give heptyl 4-iodobenzoate (2a) (14.5 g, yield 97%) as an oily liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C1COCC1.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ccc(OCc3ccccc3)cc2)c(N)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) in acetic acid (10 mL) and THF (10 mL) was added zinc (2.59 g) at 0° C., and the mixture was stirred at 0° C. for 2 h. After stirring at room temperature overnight, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with AcOEt, washed with sat. NaHCO2, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% AcOEt in hexane) to give N2-[4-(benzyloxy)phenyl]-5-methylpyridine-2,3-diamine (0.63 g) as a blue solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](Cl)[CH:10](C)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[CH3:21]N(C)C=O>>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:21][N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH2:10][C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCNCC
Reactant: CC1C(=O)N(Cc2ccccc2)CC1Cl
Product: CCN(CC)CC1CC(=O)N(Cc2ccccc2)C1

Procedure:
A mixture of 14 g (0.06 mol) of crude 1-benzyl-4-chloro-methyl-pyrrolidin-2-one, prepared as in Example 1(a), 10 g of diethylamine and 50 ml of dimethylformamide was stirred or shaken for 2 hours at 150° C. in an autoclave. The reaction mixture was evaporated to dryness in vacuo, the residue was taken up in methylene chloride, and the solution was washed first with water and finally the title compound was extracted twice with 25 ml of 2 N HCl. The aqueous phase was separated, made alkaline with sodium hydroxide and the organic base was extracted with methylene chloride. The methylene chloride phase was evaporated, and the residue was distilled in vacuo.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:32]2[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:11][CH:10]=1>O1CCCC1.C(N(CC)CC)C.ClCCl.[Cu]I.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>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:32]2[CH:33]=[CH:34][C:35]([C:7]#[C:6][CH2:5][NH:4][CH:1]3[CH2:3][CH2:2]3)=[CH:36][CH:37]=2)=[CH:16]/[CH2:17][O:18][C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:21]([CH3:31])[CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCNC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCNC3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Cyclopropyl-N-(prop-2-ynyl)amine (105 mg, 1.103 mmol) was added to a solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (336 mg, 0.613 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL). The mixture was degassed and copper(I) iodide (19 mg, 0.1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were added. The reaction mixture was stirred at ambient temperature for 2 days, diluted with dichloromethane (40 mL), washed with water (2×15 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(N-cyclopropylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate as oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([NH:12][CH:13]([C:20]([C:22]3[CH:26]=[C:25]([Cl:27])[S:24][CH:23]=3)=[O:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH:8]=[CH:9][C:2]1=2.P(Cl)(Cl)(Cl)=O.O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:21][C:20]([C:22]4[CH:26]=[C:25]([Cl:27])[S:24][CH:23]=4)=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: CCOC(=O)CC(NC(=O)c1ccc2occc2c1)C(=O)c1csc(Cl)c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc3occc3c2)oc1-c1csc(Cl)c1
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of the resulting crude product of ethyl 3-[(5-benzo[b]furoyl)amino]-4-(5-chlorothiophen-3-yl)-4-oxobutyrate (896 mg) in N,N-dimethylformamide (7 ml) was added phosphoryl chloride (0.48 ml) at room temperature, and the mixture was stirred at the same temperature overnight. To the reaction mixture was added water, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:acetone=7:1), and then, triturated with diethyl ether to obtain ethyl 2-(5-benzo[b]furyl)-5-(5-chloro-thiophen-3-yl)oxazol-4-ylacetate (349 mg) as colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:23]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:3]([CH:2]=[O:23])[O:4][CH:5]=1
Reactant: O
Reactant: FC(F)(F)c1coc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc(C(F)(F)F)co1
Temperature: -78 °C

Procedure:
A mixture of 2-bromomethyl-4-trifluoromethyl-furan (500 mg, 3.57 mmol), hexamethylenetetramine (HMTA) (637 mg, 4.54 mmol) and water (2.6 mL) were placed in a 50 mL pear-shaped flask equipped with a vigreaux column atop of which is attached to dry-ice condenser chilled at −78° C. The mixture was heated at reflux for 1 h, and then treated with concentrated HCl (1.7 mL). Reflux was maintained for an additional 1 h before the reaction was cooled to rt, diluted with water and extracted with DCM (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4) and carefully concentrated to give 4-(trifluoromethyl)furan-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (m, 1H), 8.01 (m, 1H), 9.74 (d, J=0.54 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:13]=[CH:14][C:15](O)=[O:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:14]/[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[O:16])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Reactant: OCC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4-Piperidinemethanol (17.7 g, 1.0 eq.), 3,5-difluorocinnamic acid (28.3 g, 1.0 eq.) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 78.2 g, 1.15 eq.) were dissolved in dichloromethane (DCM, 700 mL). Triethylamine (TEA, 46.6 g, 3.0 eq.) was added and the resulting solution was stirred at room temperature overnight. LCMS showed 100% conversion. The reaction mixture was concentrated and purified via silica gel column eluting with 0-75% ethyl acetate in hexanes to afford the product as a white solid (35 g, 81%). MS (ES) m/e 282 [M+H]+.
Reaction SMILES: [CH:1]#[C:2]C.C=C=C.[CH3:7][C:8]([CH3:15])=[CH:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13].C#C>>[CH3:13][C:12]([OH:14])([CH2:11][CH2:10][CH:9]=[C:8]([CH3:15])[CH3:7])[C:1]#[CH:2]
Reactant: C#CC
Reactant: CC(=O)CCC=C(C)C
Agent: C#C
Agent: C=C=C
Product: C#CC(C)(O)CCC=C(C)C

Procedure:
The invention's composition of matter, and the (Z)-4,8-dimethyl-2,7-nonadien-4-ol essentially pure, can be prepared according to several methods. As reported in the experimental part, one possibility is the addition of prop-1-yn-1-yl Grignard such as prop-1-yn-1-yl magnesium bromide to 6-methyl-5-hepten-2-one. The triple bond of 4-8-dimethylnon-7-en-2-yn-4-ol obtained is then reduced under appropriate conditions in to order to provide selectively (Z)-4,8-dimethyl-2,7-nonadien-4-ol (e.g. Lindlar catalyst). The same intermediate could also be synthesized by the addition of propyne (or allene) to 6-methyl-5-hepten-2-one under basic conditions as described in DE2228333. Another approach starting from the same starting material as above passes through the acetylene addition providing the 3,7-dimethyloct-6-en-1-yn-3-ol then the methylation of the triple bond and finally, as previously described, the stereoselective hydrogenation of the triple bond (e.g. Lindlar catalyst) leading to (Z)-4,8-dimethyl-2,7-nonadien-4-ol. The addition of acetylene or ethynyl Grignard to 6-methyl-5-hepten-2-one is well documented (as non limited literatures: WO 20075025 or J. Am. Chem. Soc. 2002, 124 (18), 5025). A more direct alternative already reported in the literature (U.S. Pat. No. 2,838,576, DE 1005952, Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences 1955, 240, 631) is the addition of the prop-1-en-1-yl Grignard to 6-methyl-5-hepten-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:12]=C=S)=[C:10]([CH3:11])[C:5]=2[N:4]=[CH:3]1.[CH2:15]([NH2:18])[CH2:16][NH2:17].[CH2:19](Cl)Cl>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:12][N:17]3[CH2:16][CH2:15][N:18]=[CH:19]3)=[C:10]([CH3:11])[C:5]=2[N:4]=[CH:3]1
Reactant: Cc1c(N=C=S)ccc2c1ncn2C
Reactant: NCCN
Reactant: ClCCl
Solvent: CO
Product: Cc1c(NN2C=NCC2)ccc2c1ncn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,4-dimethyl-5-benzimidazolylisothiocyanate (210 mg) in methylene chloride (40 mL) is added dropwise over 20 minutes to ethylenediamine (0.35 mL) in solution in methylene chloride (100 mL). The mixture is stirred for 1 hour at room temperature, then rotary evaporated. The residue is dissolved in methanol (70 mL), mercuric acetate (395 mg) is added, and the mixture is stirred at room temperature for 2 hours. The resulting black suspension is filtered on Celite with methanol wash of the solids. The filtrate is rotary evaporated, and the residue is purified by flash chromatography on silica gel, eluting with 10% methanol/chloroform containing 0.1% of ammonium hydroxide. The product-containing fractions are combined and rotary evaporated to yield 1,4-dimethyl-5-(2-imidazolinylamino )benzimidazole.HOAc.
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:5])[CH:3]=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:5][C:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)([CH3:1])[CH2:3][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)C=O)s1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CN2CCCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-2-oxo-ethyl)-[1,3,4]thiadiazol-2-yl]-amide (22 mg), pyrrolidine (0.02 ml), acetic acid (0.01 ml) in methylene chloride (1 ml) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (28 mg) was added. The mixture was stirred at room temperature for at least two days. The mixture was quenched with diluted NaOH and extracted with methylene chloride. The organic layer was separated, concentrated to dryness and the residue was purified by silica gel column chromatography using 35% to 65% ethyl acetate in hexane as eluent to give the title compound. The title compound was prepared as the corresponding HCl salt by adding HCl/doxane, followed by concentration to give a solid. LC_MS retention time 2.0 min M+1=480.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (2.07 g, 10.7 mmol) in acetone (25 mL) was added 1,3-propane sultone (1.41 g, 11.8 mmol). The mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirres at reflux for 5 minutes before 25 mL of cold acetone was added. The solid material was filtered and washed with acetone (2×25 mL). This allowed the isolation of compound J, 1.48 g (44%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](O)=[O:29])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]=C=NCC.C1(N)CCCCC1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:28](=[O:29])[NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH3:32])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)O)c3c2CCCC3)CC1
Agent: Cl
Solvent: NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCNC(=O)c1ccc(S(=O)(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Carboxy-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (76 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) was added followed by cyclohexylamine (21 mg, 24 ml, 0.21 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (15 ml0 and charged to a separatory funnel. The organic layer was washed twice with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a clear oil that was subjected to flash column chromatography (96:4 dichloromethane:methanol). Concentration of the more polar fractions afforded 4-[4-(3-dimethylamino-propylcarbamoyl)-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino]-piperidine-1-carboxylic acid tert-butyl ester (F-30) as a yellow solid. Wt.: 40 mg, (45%). 1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 7.98 (d, 1H), 7.31 (d, 1H), 5.02 (d, 1H), 3.96 (m, 3H), 3.37 (m, 2H), 3.20 (m, 2H), 2.83 (m, 4H), 2.70 (s, 6H), 2.14 (m, 2H), 1.97 (m, 2H), 1.83 (m, 4H), 1.42 (s, 9H), 1.32 (m, 4H); LC/MS m/z 523 (M+H)+. Concentration of the less polar fractions afforded 4-(4-cyclohexylcarbamoyl-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (F-31) as a clear oil. Wt.: 28 mg (32%) 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 1H), 7.20 (d, 1H), 5.73 (d, 1H), 4.38 (d, 1H), 3.91 (m, 3H), 3.22 (m, 1H), 3.12 (m, 2H), 2.89 (m, 2H), 2.73 (m, 2H), 2.03 (m, 2H), 1.78 (m, 8H), 1.74 (m, 2H), 1.43 (s, 9H), 1.27 (m, 6H); LC/MS m/z 518 (M−H)31 .
Reaction SMILES: C(OC([NH:8][C:9](=[NH:34])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:9]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][CH:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1)(=[NH:8])[NH2:34]
Reactant: COc1ccc(OCC(=O)O)c(C(Nc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OCC(=O)O)c(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c1

Procedure:
356 mg of (RS)-[4-(tert-butoxy carbonylamino-imino-methyl)-phenylamino]-(2-carboxymethoxy-5-methoxy-phenyl)-acetic acid were stirred in 3.7 ml of methylene chloride and 3.7 ml of TFA for one hour. The reaction mixture was evaporated in a vacuum and the residue was chromatographed on silica gel with ethyl acetate-acetone-water-acetic acid (6:2:1:1). From ethyl acetate-acetone-water-acetic acid (12:2:1:1) there was obtained crystalline (RS)-(4-carbamimidoyl-phenylamino)-(2-carboxymethoxy-5-methoxy-phenyl)-acetic acid, m.p. 213° C. MS: 374 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25]O)=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:66]>C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][Br:66])=[C:15]1[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCc1c(CCO)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1c(CCBr)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A solution was made with 1 eq 2-[1-benzhydryl-2-({[tert -butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl]ethanol and CH2Cl2 (0.12M). Then 0.76 eq of 1,3-bis(diphenylphosphino)propane was added and the solution was cooled to 0° C. under N2. Then 1.3 eq of CBr4 was added to give a light yellow solution. The reaction was allowed to return to room temperature. After three hours and 15 minutes the solvent was removed. Purified using a flash column with silica gel and 1:5 EtOAc/Hexane as eluent to give 1-benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indole (yellow-brown gum) in 90% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)c1nc(CCl)co1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)co1
Temperature: 35 °C
Reaction time: 17 h
Yield: 98.9 %

Procedure:
4-(Chloromethyl)-2-isopropyloxazole (0.920 g, 5.75 mmol, 1 eq) was suspended in DCM (9 mL). DIPEA (2.5 mL, 14.4 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (2.350 g, 12.6 mmol, 2.2 eq). The reaction mixture was stirred at 35° C. for 17 h, then diluted with EtOAc, washed with H2O, and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound (1.760 g, 99%); 1H-NMR (500 MHz, CDCl3): δ 1.33 (d, J=5.5 Hz, 6H, iPr—CH3), 1.45 (s, 9H, C(CH3)3), 2.45 (br t, J=4.8 Hz, 4H, piperazine N(CH2)2), 3.07 (m, 1H, iPr—CH), 3.41-3.50 (m, 6H, piperazine N(CH2)2 and NCH2), 7.41 (s, 1H, oxazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=2.51 min—310 [(M+H)+, 100%].
Reaction SMILES: [C:1]([C:5]1([CH:8]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH3:9])[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>COCCOCCOC.O.[OH-].[Li+]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:7][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([OH:6])[CH:8]([CH3:9])[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:18][CH:17]=1
Reactant: CC(n1cncn1)C1(C(C)(C)C)CO1
Reactant: Oc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: CC(n1cncn1)C(O)(COc1ccc(F)cc1)C(C)(C)C
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A mixture of 10.0 g of 2-tert-butyl-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]-oxirane, 6.4 g of 4-fluorophenol and 0.1 g of lithium hydroxide hydrate in 10 ml of diethylene glycol dimethyl ether is heated for 18 hours to 150° C. After it has cooled, the reaction mixture is poured into ice-water and extracted with ether. The organic phase is washed with water and a saturated solution of sodium chloride, dried and concentrated. Chromatography over silica gel with a 3:1 mixture of ethyl acetate/toluene as eluant yields 11.0 g of 1-(4-fluorophenoxy)-2-tert-butyl-2-hydroxy-3-methyl-3-(1H-1,2,4-triazol-1-yl)propane with a melting point of 85°-100° C. (compound 18).