Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C:15]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:16]=1[OH:17])[CH2:13][CH3:14]>OS(C(F)(F)F)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:18]2[CH:19]=[CH:20][C:21]([OH:22])=[C:15]([CH2:12][CH2:13][CH3:14])[C:16]=2[OH:17])=[O:11])=[CH:6][CH:7]=1
Reactant: CCCc1c(O)cccc1O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)Cc2ccc(Cl)cc2)c1O

Procedure:
Using the procedure in Example 51, step 1, 4-chlorophenyl-acetic acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 4-(4-chlorophenylacetyl)-1,3-dihydroxy-2-(n-propyl)benzene.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:32][C:33]([CH:35]1[CH2:37][CH2:36]1)=[NH:34]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]1[O:5][N:34]=[C:33]([CH:35]2[CH2:37][CH2:36]2)[N:32]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N=C(NO)C1CC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 500 mg Z-Pro-OH in 6 ml DMF was added a solution of 325 mg 1,1′-carbonyldiimidazole in 2 ml DMF. After stirring for 30 minutes a solution of 201 mg N-Hydroxy-cyclopropanecarboxamidine in 2 ml DMF was added and the solution stirred for 12 h at room temperature until LCMS showed complete conversion to the intermediate O-acyl amide oxime. Further 325 mg CDI were added and the mixture stirred at 115° C. for 5 h. It was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude product as colorless oil. Yield: 228 mg.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.[CH2:25]=[O:26].[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[C:10]([CH2:25][OH:26])=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)c(CO)c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl [(1S)-2-(6-hydroxy-1H-indazol-1-yl)-1-methylethyl]carbamate (30.83 g, 0.0949 mol) in THF (400 ml) was treated with aqueous concentrated formaldehyde (37%, 12 M. 0.285 mol, 24 mL) and cooled in an ice bath. To the mixture was slowly added aqueous 1 N sodium hydroxide (0.02 mol, 20 mL) and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was quenched with aqueous saturated sodium bicarbonate (250 mL) and then neutralized to pH 7 with aqueous 2 N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL×3), the combined organic layers were dried over magnesium sulfate and filtered and evaporated to give crude tan solid, 28.38 g, which was a mixture of desired product and dimerized byproduct by LC/MS 356 m/z and 663 m/z. This residue was purified by chromatography (silica gel, hexane/ethyl acetate 1:1) to give the title compound, (18.44 g, 56%) as a yellow foamy solid, which was not pure by LS/MS 354 m/z with minor 663 m/z.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O=[S:10](Cl)Cl.Cl.[C:14](=[NH:17])([NH2:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[S:10][N:16]=[C:14]([CH3:15])[N:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(=N)N
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nsc(-c2ccc(Cl)nn2)n1
Temperature: 74 °C
Reaction time: 1 h

Procedure:
To 3-chloro-6-methylpyridazine (5 g, 39 mmol) was added SOCl2 (29 mL) and the resulting mixture was heated at 73-75° C. for 20 h. The resulting mixture then was concentrated and the residue was dried in vacuo for 30 min. The residue was then dissolved in CH2Cl2 (80 mL) and ethanimidamide hydrochloride (3.69 g, 39 mmol) was added. 50% NaOH(aq) (10 mL) was then added dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for another 1 h. The resulting mixture was then poured into CH2Cl2/H2O (100 mL/200 mL). The aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column using EtOAc/CH2Cl2/hexane (40/10/50) as the eluent to yield 5-(6-chloropyridazin-3-yl)-3-methyl-1,2,4-thiadiazole.
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[F:18])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[F:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:19]
Reactant: CC(Cn1ncc2c1=CC1=C(F)C=CCC=21)N=[N+]=[N-]
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: CC(N)Cn1ncc2c1=CC1=C(F)C=CCC=21
Temperature: 25 °C
Yield: 78.3 %

Procedure:
1.59 g (6.18 mmol) of (RS)-1-(2-azido-propyl)-7-fluoro-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 14 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 717 mg (6.18 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for S hours and the white crystals were subsequently filtered off. 1.68 g (78%) of (RS)-2-(7-fluoro-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 168°-170° were obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16]1([CH:22]([CH3:26])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: CC(C(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C(C)c2ccccc2)cn1
Yield: 64.5 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (300 mg, 1.3 mmol), 2-phenylpropanoic acid (225 mg, 1.5 mmol), triethylamine (300 mg, 3 mmol), DMAP (61 mg, 0.5 mmol), and EDC (386 mg, 2 mmol) were stirred together in DCM (10 mL) at room temperature for 4 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated, on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-phenylpropanamide (272 mg, 81%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, 3H, J=7.2 Hz), 2.10 (s, 3H), 2.37 (s, 3H), 3.70 (m, 1H, J=6.8 Hz), 5.06 (s, 2H), 7.20 (t, 1H, J=8.4 Hz), 7.31-7.28 (m, 4H), 7.38 (s, 1H), 7.91 (s, 1H), 10.10 (s, 1H). LC/MS; [M+H] calculated for C18H20N4O2; expected 325.16; found 325.5. Melting point: 129-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([CH2:36][N:37]2[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O.C(N(CC)CC)C>[CH:30]1([CH2:36][N:37]2[CH2:41][CH2:40][CH:39]([NH:42][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=3[O:2][CH3:1])[CH2:38]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: NC1CCN(CC2CCCCC2)C1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NC2CCN(CC3CCCCC3)C2)c1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 53.2 %

Procedure:
7.85 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3 g of triethylamine are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to 0° and 4.2 g of isobutyl chloroformate is poured in drop by drop. The mixture is agitated for 45 minutes at 0° C., after which 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine is dripped in. It is agitated for 2 hours at room temperature, then 80 ml of water is added and the acetone evaporated under vacuum. The product crystallises. It is filtered, washed with water then re-dissolved in 150 ml of water and 20 ml of hydrochloric acid. The solution is filtered with charcoal and the filtrate made alkaline with ammonia. An oil is precipitated and crystallises slowly. The crystals are drained, washed with water and dried in an oven at 50° C. 6.8 g (53%) of product is obtained, with a melting point of 167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Brc1ccc(NCc2cccnc2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Br)cc1

Procedure:
Using the procedure of Example 343 using N-(4-bromophenyl)pyridin-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate gave the title compound. Anal Calcd for C14H15BrN2O2S: C, 47.33; H, 4.26; N, 7.88. Found: C, 47.24; H, 4.23; N, 7.79. MS found 354.0, 355.9 FD.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[C:12]([SH:14])#[N:13].N.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:13][C:12]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[S:14])=[O:5]
Reactant: N#CS
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: N
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1ccc(Cl)c(Cl)c1)c1c(Cl)cccc1Cl
Reaction time: 0.25 h

Procedure:
10.5 g of 2.6-dichlorobenzoylchloride are added drop by drop with stirring to a solution of 3.8 g of ammonium rhodanide in 15 ml of acetone. After boiling for 15 minutes the reaction mixture is added drop by drop to a solution of 8.1 g of 3,4-dichloroaniline in 15 ml of acetone. After stirring for 30 minutes the reaction mixture is poured in water and extracted with ether. The ethereal solution is dried and concentrated by evaporation and the residue is taken up in benzene. After working up and decrystallizing from benzene 1.3 g of the superscribed substance is obtained. Melting point 240° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C(Cl)(Cl)Cl.O>[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[N:8]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(I)cc1F
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Thiophosgene (3.55 mL, 46.4 mmol) was added to a rapidly-stirred mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) in CHCl3 (200 mL) and water (100 mL). The mixture was stirred at r.t. for 16 h. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white crystalline solid (11.8 g, quant.). δH (DMSO-d6) 7.87 (1H, dd, J 1.8, 9.5 Hz), 7.63 (1H, ddd, J 1.0, 1.8, 8.4 Hz), 7.25 (1H, dd, J 8.2, 8.4 Hz).
Reaction SMILES: [CH3:1][N:2]([S:42]([CH3:45])(=[O:44])=[O:43])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])=[O:32])[CH:30]=1)[C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:10]([O:14]C1CCCCO1)[C:11]([OH:13])=O)=[O:7].[NH2:46][C:47]1[NH:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:21]([C@H:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([N:2]([CH3:1])[S:42]([CH3:45])(=[O:44])=[O:43])[CH:30]=[C:29]([C:31]([NH:33][C@@H:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])=[O:32])[CH:28]=1)[C@@H:10]([OH:14])[C:11]([NH:46][C:47]1[NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[CH:55][C:49]=2[N:48]=1)=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](OC2CCCCO2)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C(=O)Nc2nc3ccccc3[nH]2)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 2 mL solution of (2R,3S)-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)benzoyl]amino}-4-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid obtained in Reference Example 27 64 mg (0.1 mmol), 2-aminobenzimidazole 27 mg (0.2 mmol), HOBt.H2O 31 mg (0.2 mmol) and 4-(dimethylamino)pyridine 2.4 mg (0.02 mmol) in N,N-dimethylformamide was added a polystyrene-supported carbodiimide (1.38 mmol/g) 181 mg (equivalent to carbodiimide 0.25 mmol) and the mixture was shaken overnight. After completion of the reaction, the mixture was filtered and the filtrate was extracted by adding ethyl acetate and 5% aqueous sodium carbonate solution. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on the magnesium sulfate, filtered and concentrated. The concentrated residue was redissolved in chloroform 2 mL and thereto was added TFA 1 mL and the mixture was stirred at room temperature for 3 hours to remove the protecting group. After completion of the reaction, the mixture was concentrated and the concentrated residue was purified by HPLC fraction collector to give 32 mg (0.05 mmol) of the title compound (overall yields: 48%).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[C:2]([NH2:4])=[NH:3].Cl.[CH2:15]([O:17][C:18](=[O:37])[CH2:19][C@H:20]([NH:32][C:33](=[O:36])[CH2:34][NH2:35])[C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([Br:31])[CH:22]=1)[CH3:16].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.ClCCl>[Br:31][C:23]1[CH:22]=[C:21]([C@@H:20]([NH:32][C:33](=[O:36])[CH2:34][NH:35][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[CH:13]=2)[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:37])[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:24]=1
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Reactant: CCOC(=O)C[C@H](NC(=O)CN)c1cc(Br)cc(C(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cccc(NC(=N)N)c1)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-guanidinobenzoic acid (Example C) (179.5 mg, 1.00 mmol), (S)-ethyl 3-(2-aminoacetamido)-3-(3-bromo-5-tert-butyl)phenyl)propanoate hydrochloride (Example H) (439.5 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (31.2 mg, 0.20 mmol) was dissolved in DMF (4 mL) and dichloromethane (4 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a colorless suspension. N,N′-diisopropylcarbodiimide (205 uL, 1.33 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in vacuo to give a yellow viscous residue of the intermediate product: (S)-ethyl 3-(3-bromo-5-(tert-butyl)phenyl)-3-(2-(3-guanidinobenzamido)acetamido) propanoate. LC-MS analysis of the crude residue shows the desired product's mass: m/z 546 (79BrM+H), m/z 548 (81BrM+H); m/z 568 (79BrM+Na) and m/z 570 (81BrM+Na); Calcd for C25H32BrN5O4: 546.46. The crude residue will be used as such for the saponification (step #2).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[F:26]>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[O:16])=[CH:21][C:20]=1[F:26]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccc(Br)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
2.9 ml of triethylamine and 1.87 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 1 g of 4-bromo-3-fluoroaniline, and stirred at room temperature for 4 hours. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain 1.44 g of the entitled compound as a pale yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1OC)[N:8]=[CH:7][NH:6][C:5]2=[O:14].[CH:15]([N:18](C(C)C)CC)([CH3:17])[CH3:16].O=P(Cl)(Cl)Cl.[CH:29](N)(C)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2([NH:18][CH:15]([CH3:17])[CH3:16])[O:14][CH3:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2nc[nH]c(=O)c2cc1Br
Reactant: CC(C)N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC1(NC(C)C)NC=Nc2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
6-Bromo-7-methoxy-3H-quinazolin-4-one (1.01 g, 3.96 mmol) and N,N-(diisopropyl-ethylamine (1.78 ml, 10.4 mmol) are introduced into 1,2-dichloroethane (19 ml), treated dropwise with POCl3 (0.46 ml, 4.95 mmol) and then stirred at 80° C. for 2 h. The reaction mixture is subsequently concentrated to dryness. The residue is taken up in isopropanol (10 ml), treated with isopropylamine (0.34 ml, 3.96 mmol) and stirred for 30 minutes at 80° C. After cooling to room temperature, the resulting precipitate is filtered off with suction and dried in vacuo. The desired product is obtained in 46% yield (530 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[OH-].[Na+].N1([NH:21][S:22](Cl)(=[O:24])=[O:23])CCOCC1.Cl.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>O>[N:21]1([S:22]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)(=[O:24])=[O:23])[CH2:27][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1CCOC1
Reactant: O=S(=O)(Cl)NN1CCOCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of L-PHE (66 g), NaOH (16 g), and water (120 mL) was treated dropwise with a solution of 4-morpholinylsulfamyl chloride (37 g, prepared according to the methods of R. Wegler and K. Bodenbenner, Anallen der Chemie, 624, 25 (1959) and G. Weiss and G. Schulze, Anallen der Chemie, 729, 40 (1969)) in THF (80 mL). The reaction was stirred for 6 hours at room temperature then concentrated aqueous HCl was added dropwise to bring the solution to pH 2. Product was extracted into EtOAc and this solution was washed with lN HCl, dried over MgSO4 and evaporated. The residue was triturated with ether to give a solid that was recrystallized from water to give morpholinylsulfonyl-PHE. MP 157°-158° C. MS (FAB) 337 (m+Na), 315 (m+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][C@@H:26]([CH3:28])[O:25][C@@H:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=2[C:38]([NH2:40])=O)=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O=P(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][C@@H:26]([CH3:28])[O:25][C@@H:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=2[C:38]#[N:40])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5C(N)=O)s4)nc23)C[C@H](C)O1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: C[C@@H]1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5C#N)s4)nc23)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.8 %

Procedure:
To a solution of the product of example 117 (15 mg, 0.024 mmol) in DMF (0.5 ml), POCl3 (0.1 ml) was added drop-wise. The mixture was stirred at room temperature for 20 hours, after which water was added, and then extracted with CH2Cl2. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography (CH2Cl2/EA/MeOH=8/2/1) to give the desired product (6 mg, 40% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15](C(O)(CCC2(C)OCC(C)(C)CO2)CO)[CH:16]=[CH:17][CH:18]=1.[CH3:34][C:35]([CH3:37])=[O:36]>>[C:35]([CH2:37][CH2:34][C:35]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH:14]=2)[CH2:37][O:12][C:13]([CH3:14])([CH3:18])[O:36]1)(=[O:36])[CH3:34]
Reactant: CC(C)=O
Reactant: CC1(C)COC(C)(CCC(O)(CO)c2cccc(OCc3ccc4ccccc4c3)c2)OC1
Product: CC(=O)CCC1(c2cccc(OCc3ccc4ccccc4c3)c2)COC(C)(C)O1
Yield: 45 %

Procedure:
Using the procedure described in Example 1, 2-[3-(naphth-2-ylmethoxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)butane-1,2-diol (0.77 g) was reacted with acetone to give 4-(2-acetylethyl)-2,2-dimethyl -4-[3-(naphth-2-ylmethoxy)phenyl]-1,3-dioxolane (0.32 g, 45%), as an oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[C:9]([O:31][CH3:32])=[C:10]([NH2:30])[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:30][C:10]1[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=[C:8]([Br:7])[C:9]=1[O:31][CH3:32]
Reactant: COc1c(N)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(Br)c1OC
Reaction time: 48 h
Yield: 71.1 %

Procedure:
Methyl bromoacetate (0.285 mL, 3.01 mmol) was added to a stirred, room temperature suspension of 3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) in DMF (1.7 mL). After two days, more methyl bromoacetate (0.135 mL, 1.5 mmol) and the reaction mixture was stirred for a day longer. The reaction mixture was added to water and the solid was filtered and washed with water. The solid was triturated with pet. ether and dried at 60° C. under vacumm to provide the title compound as a white solid (0.212 g, 71%): mp 194-198° C.: NMR (DMSO-d6); 8.17 (dd, J=8, 1 Hz, 1H), 7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.53-7.45 (m, 2H), 6.77 (d, J=2 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.10 (t, J=7 Hz, 1H), 3.97 (dd, J=7, 4 Hz, 2H), 3.83 (s, 3H), 3.52 (s, 3H),2.43 (s, 3H), 1.69 (s, 3H); MS (FAB+): 2 bromine isotope pattern 561, 563, 565; Anal. Calc. for C24H21Br2NO3S: C, 51.17; H, 3.76; N, 2.49. Found: C, 50.43; H, 3.63; N, 2.53.