Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=2/[C:10](=[N:24]/[NH:23][C:20]([NH2:22])=[NH:21])/[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1ncnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1ncnc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 141.9 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinazolin-5-one (40 mg) and aminoguanidine hydrochloride (16 mg) were added ethanol (3 ml) and 6N hydrochloric acid (0.025 ml), and the mixture was stirred at 90° C. for 3 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinazoline hydrochloride (Compound 89) (38 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)Cl)cc1

Procedure:
A solution of 4-(dimethylamino)benzoic acid and thionyl chloride in methylene chloride was refluxed 4 h. Volatile solvents were removed in vacuo to yield 1.10 g of 4-(dimethylamino)benzoyl chloride. This material was used in subsequent reactions without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C[Li].Cl[C:13]1C(Cl)=C(O)C(C#N)=C(C#N)C=1O.[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:13])[N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N
Reactant: CSc1nccc(Cl)n1
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CSc1nc(C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.93 mL of 4-chloro-2-methylthiopyrimidine was dissolved in 50 mL of diethyl ether, and 100 mL of methyllithium (1M diethyl ether solution) was gradually added to the solution at −78° C. The reaction solution was stirred at 0° C. for 1 hour, and then a solution prepared by mixing 2.3 mL of water and 15 mL of tetrahydrofuran was added thereto. The reaction solution was stirred at the same temperature for 10 minutes, and then 50 mL of a tetrahydrofuran solution containing 13.7 g of 2,3-dichloro-5,6-dicyanohydroquinone was added thereto. The reaction solution was stirred at the same temperature for 1 hour, and then 100 mL of a 1 N aqueous solution of sodium hydroxide was added to the reaction solution. The obtained reaction solution was extracted with hexane, and the organic layer was washed with a 1 N aqueous solution of sodium hydroxide and saturated brine. After drying over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5.1 g of 4-chloro-6-methyl-2-(methylthio)pyrimidine [42-1] as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][Br:11])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1F
Yield: 63.1 %

Procedure:
A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2′-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.Cl.[CH3:13][NH2:14]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:14][CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CN
Agent: Cl
Solvent: CS(C)=O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.7 mmol) in DMSO (50 mL) was added TEA (18.47 g, 183 mmol), methylamine hydrochloride (6.1 g, 91.4 mmol) and the reaction mixture was heated under microwave conditions at 120° C. for 3 h. The mixture was cooled, extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude product was used in next step without further purification. (10.5 g, yield 98%) MS (ESI+) e/z: 231.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 65 mg (0.14 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH2Cl2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH2Cl2. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 THF-EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 63 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.46(br. s, 1H); 9.33(br. s, 1H); 7.96(s, 2H); 7.03(t, 1H, J=7.7 Hz); 6.55-7.08(m, 3H); 3.75(s, 2H); 3.19-3.36(m, 1H); 1.29(d, 6 H, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[F:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[C:15]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: Fc1cnccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 150 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 1.59 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 1.22 g of 4-(chloromethyl)-3-fluoropyridine, 3.48 g of potassium carbonate and 7 ml of DMF was stirred at 80° C. for 1 hour and subsequently at 150° C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.27 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]-pyridine (hereinafter, referred to as “Present Active Compound 8”).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1(C)[O:12][C:10](=[O:11])[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].B(F)(F)F.[CH3:18]OC1C=CC(O)=CC=1>C(OCC)(=O)C>[C:1]([O:6][C:7]1([CH3:18])[CH2:8][O:12][C:10](=[O:11])[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1(C)CC(=O)O1
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OC1(C)COC(=O)C1

Procedure:
In a 50 mL four-necked flask, 0.5 g of β-methacryloyloxymethyl-β-methyl-β-propiolactone was put, and dissolved in 10 g of ethyl acetate, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. Then, 5 mol % of diethyl ether complex of boron trifluoride was added thereto based on the substrate, and 5 mg of p-methoxyphenol was added thereto, and while solution temperature was kept at 30° C., the resulting mixture was stirred. After the mixture was stirred for 2 hours, the resulting reaction mixture was washed with a 10% sodium carbonate aqueous solution and saturated brine, and dried over magnesium sulfate. After separation by filtration, the solvent was distilled off using an evaporator. Consequently, 0.42 g of crude β-methacryloyloxy-β-methyl-γ-butyrolactone represented by formula (8) was obtained, and a quantitative isomerization reaction was confirmed by HPLC and NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C=CCO
Product: COC(=O)c1ccc(CCC=O)cc1

Procedure:
A process disclosed in U.S. patent application Ser. No. 10/302,636 for making 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid may be summarized as follows: methyl-4-iodobenzoate is reacted with allyl alcohol to provide 4-(3-Oxo-propyl)-benzoic acid methyl ester, which is then reacted with 5-chloro-2-methylindole to yield 4-[3-(5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester; this product is reacted with benzhydryl bromide to produce 4-[3-(1-benzhydryl-5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester, which is then reacted with benzoyl peroxide to produce the 2-formyl indole; the 2 formyl indole is then reacted with nitromethane followed by Zn(Hg)/HCl to form the 2-(2-aminoethyl) indole; this amine is then reacted with [(3,4-dichlorophenyl)-methyl]sulfonyl chloride to produce 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid methyl ester, which is then hydrolyzed to form 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid. In this process, chromatography is used to separate some of the compounds made in the aforesaid reactions. It would be desirable to have a process for making the product that does not require the use of chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]1([C@H:47]([NH:49][C:50]([NH2:52])=[O:51])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1.C(Cl)Cl>[CH3:34][O:33][C:11]1[C:5]2[C:6]([CH2:8][O:9][CH3:10])=[N:7][C:2]([NH:52][C:50]([NH:49][C@@H:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:48])=[O:51])=[CH:3][C:4]=2[NH:13][N:12]=1
Reactant: COCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(OC)c12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
BrettPhos pre-catalyst (6.80 mg, 8.51 μmol), 6-chloro-3-methoxy-4-(methoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (40 mg, 0.085 mmol), cesium carbonate (83 mg, 0.255 mmol), and (R)-1-(1-phenylethyl)urea (20.96 mg, 0.128 mmol) were taken up in dioxane (1 mL) in a 1.5 mL microwave vial and the vial was evacuated and back-filled with N2 (×3). The reaction mixture was stirred at 90° C. for 2 h. The crude reaction mixture was diluted with DCM, filtered through a syringe filter, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL), charged with triethylsilane (100 uL), and stirred at room temperature for 10 min. The reaction mixture was concentrated in vacuo and the residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS—HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-methoxy-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356. 1H NMR (500 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 7.25 (m, 4H), 6.86 (s, 1H), 5.02 (br s, 2H), 5.01-4.98 (m, 1H), 4.10 (s, 3H), 3.58 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[N:15]#[C:16]Br>C(O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:16]([NH2:15])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: N#CBr
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(N)nc3cc21

Procedure:
3.00 g. (0.016 mole) 5,6-diamino-3,3-dimethylindolin-2-one are suspended in 100 ml. ethanol and mixed at ambient temperature with 1.82 g. (0.017 mole) cyanogen bromide and stirred for 2 hours. The solvent is removed in a vacuum and the residue is dissolved in ethanol, treated with active charcoal and the product precipitated out by the addition of acetone. The product is crystallised from acetone and a little ethanol to give 1.05 g. (22% of theory) of the title compound in the form of the hydrobromide; m.p. 300°-305° C.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1.O>C1(C)C=CC=CC=1>[Br:2][CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1
Reactant: CC1(C)CC(CO)Sc2ccccc21
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(CBr)Sc2ccccc21
Reaction time: 1 h
Yield: 88 %

Procedure:
Phosphorus tribromide (1 ml, 10.7 mmol) is added drop by drop with a syringe at between 20 and 25° C. to a solution of the previous 6-(hydroxymethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane (1.85 g, 8.9 mmol) in 6.2 ml of anhydrous toluene. The mixture was left to agitate for 1 hour and then hydrolysed at 0° C. by ice and then by water. This was then extracted with ethyl ether, dried over MgSO4, filtered and the solvents evaporated. 2.14 g of 6-(bromomethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane is obtained (gross yield=88%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: CNCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1ccccc1Cl
Yield: 31.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzoyl chloride (76 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 9.8/2 as eluent) to afford 37 mg of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a brown oil (Yield: 31%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH2:7]2.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][O:6][CH2:7]3)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Brc1cccc2c1CCOC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCOC3)CC1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A third intermediate compound, 1-Isochroman-5-yl-piperazine, was produced as follows: To a mixture of 5-bromo-isochroman (1 g, 4.69 mmol), 1-boc-piperazine (1.05 g, 5.6 mmol), 2-dicyclohexylphosphino biphenyl (0.066 g, 0.19 mmol), and Pd(OAc)2 (0.42 g, 0.19 mmol) in 10 mL of dry degassed C6H5CH3 was added NaOtBu (0.63 g, 6.6 mmol) at room temperature. The resulting mixture was stirred at 80–90° C. for 1 h, cooled and passed through a pad of celite and the filtrate was concentrated under vacuum. The residue was purified by chromatography (25–50% EtOAc/hexanes) to give 4-isochroman-5-yl-piperazine-1-carboxylic acid tert-butyl ester (0.89 g, 60%). MS (ES) m/z: 319.19 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 4.79 (s, 2H), 3.94 (t, J=5.9 Hz, 2H), 3.55 (br s, 4H), 2.86–2.80 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3n[nH]c(-c4ccc(F)cc4)n3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc(-c3ccc([C@H]4CNCCO4)cc3)n[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)-tert-Butyl 2-(4-(5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine-4-carboxylate (28 mg, 0.066 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 0.2 ml, 0.79 mmol) was added. The reaction mixture was stirred at 60° C. for 2 h. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)phenyl)morpholine hydrochloride (26 mg, 99%) as a white solid. MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.C[O:27][C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1>>[Cl:38][C:33]1[CH:32]=[C:31]([CH2:30][C@H:29]([NH:39][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=2[NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[C:28]([OH:27])=[O:40])[CH:36]=[CH:35][C:34]=1[Cl:37]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
4-Iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid was coupled with (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in Example 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.05 min. MS (ESI−): mass calcd. for C24H17Cl2IN4O5S, 671.29; m/z found, 669/671 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.86 (s, 1H), 9.01 (d, J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.55 (dd, J=7.3,1.0, 1H), 8.32 (dd, J=8.5, 1.0, 1H), 8.08 (d, J=1.3, 1H), 7.91-7.88 (m, 1H), 7.34 (d, J=8.2, 1H), 7.30-7.24 (m, 2H), 6.98 (dd, J=8.2, 1.9, 1H), 6.88 (d, J=8.2, 1H), 6.38 (d, J=7.3, 1H), 4.90 (q, J=5.9, 1H), 3.28-3.12 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH2:19]([OH:22])[C:20]#[CH:21]>C(#N)C.[Cu]I>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:21]=[C:20]([CH2:19][OH:22])[N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC#N
Product: O=C1O[C@@H](Cn2cc(CO)nn2)CN1c1ccc(I)c(F)c1
Yield: 105.1 %

Procedure:
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (Intermediate 5, 10 g, 28 mmol) was dissolved in acetonitrile (80 mL). Propargyl alcohol (3.2 mL, 56 mmol) was added and then CuI (526 mg, 2.8 mmol) and it was stirred overnight. The solidified reaction mixture was extracted with ethyl acetate/acetonitrile, washed with water and dried over magnesium sulfate. Evaporation of solvent under vacuum gave 12.3 g crude product (quantitative).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])=[CH:12][CH:13]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(OCCO)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OCCO)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
4-(2-Hydroxy-ethoxy)-benzoic acid (152 mg, 0.84 mmol), (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (193 mg, 1.25 mmol) and triethylamine (303 mg, 3.0 mmol) are dissolved in dichloromethane (5.0 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (786 mg, 1.5 mmol) is added to the mixture. The mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with dichloromethane, washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified using silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1) to give 177 mg (66%) of the title compound. Observed Mass 319.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:19])[CH2:8][CH2:7][C:6]([N:16]([CH3:18])[CH3:17])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:38])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH3:17][N:16]([CH3:18])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:5][CH2:4][C:3]([CH2:2][NH:1][C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:19])[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C)(CN)CC1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(CNC(=O)/C=C/c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the title compound of step 4 (polar diastereomer) (250 mg, 0.94 mmol) and Hünig's base (169 μl, 1.0 mmol) in abs. dichloromethane (10 mL) was mixed with cinnamic acid chloride (166 mg 1.0 mmol) and stirred for 24 h at RT. The organic solution was washed with saturated NaHCO3 solution and saturated NaCl solution, dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 4:1.