Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][C@H:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:60]1[C:65](=[O:66])[CH2:64][CH2:63][C:61]1=[O:62])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[C:13]([O:12][C:10](=[O:11])[C:9]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][C@H:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][C:35]([O:37][N:60]2[C:65](=[O:66])[CH2:64][CH2:63][C:61]2=[O:62])=[O:36])[CH:19]=[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:46])[CH:8]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)N[C@@H](CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
5-[9-((S)-1-tert-Butoxycarbonyl-3-carboxy-propylcarbamoyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (70 mg, 0.11 mmol) was dissolved in dry THF (1 ml). TSTU (40 mg, 0.13 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred at room temperature under nitrogen over the weekend. The mixture was concentrated. The residue was redissolved in EtOAc and filtered. The filtrate was washed with 0.1N HCl (2×), washed with brine (1×), dried (Na2SO4) and concentrated to give a clear syrup. There was still starting material present and the TSTU-treatment was repeated followed by work up to give the title compound as a clear syrup.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([Cl:25])[N:16]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:21]([C:19]1[CH:18]=[C:17]([Cl:25])[N:16]=[C:15]([CH2:14][N:2]([CH3:3])[CH3:1])[CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(Cl)nc(CBr)c1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
Stir a solution of 2N dimethylamine (9.00 mL, 18.08 mmol) in tetrahydrofuran, N,N-diisopropylethylamine (2.80 g, 3.80 mL, 21.69 mmol) while adding a solution of 2-bromomethyl-4-tert-butyl-6-chloro-pyridine (1.90 g, 7.23 mmol) in tetrahydrofuran (20 mL). Stir for 2.5 hours at ambient temperature, dilute the reaction with aqueous sodium bicarbonate (80 mL) and extract the aqueous layer with ethyl acetate (3×75 mL). Pool, desiccate, filter and concentrate the organics to yield the title compound (99%) (1.64 g, 7.23 mmol). MS(ES), m/z 227 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]#[CH:12]>>[CH2:12]([C:3]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=C(O)C1CCCC1=O
Product: C#CCC1(C(=O)O)CCCC1=O

Procedure:
Alternatively, a lower alkyl ester of 2-oxocyclopentanecarboxylic acid can be condensed with e.g. propargyl bromide to yield the lower alkyl ester of 1-(2-propynyl)-2-oxocyclopentanecarboxylic acid which is then reacted as described above to yield the corresponding ester of 4-(3-cyanopropyl)-6-heptynoic acid which is then reacted with 3-bromopyridine under conditions of the modified Heck reaction as described by D.E. Ames et al., Synthesis 1981, 364 to yield the ester of 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptynoic acid which is hydrogenated under conditions known in the art, e.g. in the presence of palladium on charcoal, to the lower alkyl ester of 8-amino-4-[3-(3- pyridyl)-propyl]-octanoic acid.
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][N:15]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:14]([CH2:13][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCOc1ccnc(CBr)c1OC
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of potassium salt of 2-mercaptobenzimidazole (0.4 g) in dimethylformamide (5 ml), was added dropwise a solution of 2-bromomethyl-3-methoxy-4-propoxypyridine (0.4 g) in dimethylformamide, and stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform (50 ml), washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)) to give 2-[(3-methoxy-4-propoxypyrid-2-yl)methylthio]benzimidazole (0.35 g) as a light brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([NH:16][OH:17])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.CN(C=O)C.C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[C@H:13]([N:16]([OH:17])[C:25]([NH2:24])=[O:26])[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON[C@@H]1COc2cc(OCc3ccccc3)ccc21
Reactant: C[Si](C)(C)N=C=O
Agent: C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)N(O)[C@@H]1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a 5 L, 3-necked flask equipped with a mechanical stirrer, thermometer and condenser with CaCl2 drying tube was added under a N2 atmosphere (S)-N-[6-benzyloxy-2,3-dihydrobenzofuran-3-yl]hydroxylamine (129.0 g, 0.501 mol) in THF (2.6 L). The resulting mixture was stirred at room temperature for 0.5 h, at which time was added in one portion, trimethylsilylisocyanate (107.2 mL, 86.6 g, 0.752 mol). The mixture was then heated at reflux for 15 min, then was cooled to 5° C. with an ice bath. The precipitate which formed was collected by filtration to afford a white solid. A second crop of peach-colored solid was obtained from concentration of the filtrate. This was taken up in a minimum of DMF, heated and treated with Darco. Filtration and cooling afforded a white solid which was collected, dried and combined with the first crop. The combined solids were dissolved in EtOH (20 vol), heated to reflux, cooled, collected and dried to afford the title compound (105.4 g, 70.2%); m.p. 192.5°-193° C.
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][CH:5]([N:7]([C@@H](C2C=CC=CC=2)C)C(=O)OCC2C=CC=CC=2)[CH:4]([NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH2:3]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:7][CH:5]1[CH2:6][C:2]([F:1])([F:34])[CH2:3][CH:4]1[NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC(F)(F)CC1NS(=O)(=O)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1N

Procedure:
A solution of benzyl N-[4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-N-[(1R)-1-phenylethyl]carbamate (130 mg, 0.26 mmol) and palladium hydroxide on carbon (20%, 100 mg, 0.14 mmol) in methanol (3.5 ml) was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
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.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:52]([C:55]1[CH:56]=[C:57]([C:61]2[N:62]=[C:63]([NH2:66])[S:64][CH:65]=2)[CH:58]=[CH:59][CH:60]=1)([O-:54])=[O:53]>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:66][C:63]1[S:64][CH:65]=[C:61]([C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([N+:52]([O-:54])=[O:53])[CH:56]=2)[N:62]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-Pro-OH (1.5 g, 6.15 mmol) and HATU (2.3 g, 6.15 mmol) were combined in 30 mL of dry DMF. To this solution was added DIEA (1.5 mL, 8.8 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 4-(3-nitro-phenyl)-thiazol-2-ylamine (0.9, 4.1 mmol). Reaction mixture was stirred at room temperature overnight. The crude material was purified using reverse phase HPLC to yield 2-[4-(3-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester. MS: 453.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:33]N1CCOCC1.ClC(OCC(C)C)=O>ClCCl>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:33])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A solution of 1-[(5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylic acid (Preparation 41) (480 mg, 1.07 mmol) and N-methylmorpholine (130 μl, 1.17 mmol) in dichloromethane (10 ml) was cooled to 0° C. and then treated with isobutyl chloroformate (150 μl, 1.17 mmol). The mixture was stirred at 0° C. for 30 minutes then allowed to warm to room temperature over 1 hour. The mixture was quenched with methanol (5 ml) and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and hydrochloric acid (1M). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (95:5) gradually changing to dichloromethane:ethyl acetate (90:10) to afford the title compound (230 mg)
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH3:29][C:30]1[CH2:34][CH:33]([CH2:35][O:36][NH2:37])[O:32][N:31]=1>>[CH3:29][C:30]1[CH2:34][CH:33]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:32][N:31]=1
Reactant: CC1=NOC(CON)C1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: CC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-methyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 89).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:32])([F:31])[F:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])=[CH:20][C:19]=1[O:28][C:29]([F:30])([F:32])[F:31]
Reactant: O=C(O)Cc1ccc(Cl)c(OC(F)(F)F)c1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(OC(F)(F)F)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 4-chloro-3-(trifluoromethoxy)phenylacetic acid (0.025 g, 0.10 mmol) and Et3N (0.060 mL, 0.43 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.039 g, 85%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.44 (m, 3H), 7.12-7.22 (m, 4H), 3.90 (s, 2H), 3.76 (m, 2H), 2.80 (t, J=6.2 Hz, 2H), 2.02 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O2 [M+H]+ 454.1, found 454.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].O>CO>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[N:21]1
Reactant: CCOC(=O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.3 %

Procedure:
Compound 169 (73 mg, 0.19 mmol) was dissolved in methanol (1.0 mL) and 2 mol/L sodium hydroxide (1.0 mol) was added, followed by stirring at room temperature for 1.5 hours. Water was added to the mixture and the organic layer was extracted with ethyl acetate and the aqueous layer was neutralized using 6 mol/L hydrochloric acid. The precipitated solid was triturated in ethyl acetate to obtain Compound 170 (14 mg, 21%).
Reaction SMILES: C(O[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[N:29]([CH3:37])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:38])=[CH:13]1)C1C=CC=CC=1.[BrH:39]>C(O)(=O)C>[Br:39][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[N:29]([CH3:37])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:38])=[CH:13]1
Reactant: Br
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCOCc3ccccc3)c3ccc(F)cc23)c2cc(F)ccc21
Solvent: CC(=O)O
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCBr)c3ccc(F)cc23)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a flask was added the compound obtained in Example 1, (1.0 g, 2.36 mmol) in acetic acid (30 mL). To this solution was added hydrobromic acid (33% in acetic acid, 8 mL), and the flask was sealed. The flask was heated with stirring in an oil bath (80° C.) for 12 hours. The reaction was monitored on LC-MS, which confirmed the completion of the reaction. The volatiles were removed in vaccuo, and the residue was partitioned between ethyl acetate and water (50+50 mL). The organic phase was washed twice with water and once with brine and evaporated to give a 1.1 g (97%) of the title compound as a crude product, pure enough to be used further without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH2:5])[CH3:2].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](=[O:16])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C(OCC)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=CC(=O)C(Cl)(Cl)Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.49 g 1-(1-Ethoxy-vinyl)-4-Fluorobenzene in 3.6 mL of Pyridine was added at 0° C. to 8.19 g of Trichloroacetyl chloride. The suspension was diluted with 15 ml of dry methylene chloride and stirred at room temperature overnight. The resulting dark brown suspension was concentrated in vaccuo, filtered over a silica gel column with a 9:1 mixture of Heptane and Ethyl acetate as eluant. One obtains after concentration 28 g of a reddish brown oil which was repurified by chromatography on silica gel using a 19:1 mixture of Heptane and Ethyl acetate as eluant. The obtained brown oil (10.15 g) was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:16])[CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)Oc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 33.3 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.027 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 60 (0.015 g, 0.03 mmol, 38%) as a white solid. LCMS m/z (%)=447 (M+H79Br, 98), 449 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.11 (s, 2H), 7.65 (dd, J=2.4, 8.9 Hz, 1H), 7.54 (dd, J=4.9, 8.7 Hz, 2H), 7.49 (s, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 4.40-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J=6.0 Hz, 3H), 1.11 (d, J=6.0 Hz, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[C:35]1([CH2:34][N:41]([CH2:15][C:13]2[CH:14]=[CH:8][CH:9]=[CH:11][CH:12]=2)[C:4]([C:6]2([C:29]([OH:31])=[O:30])[O:10][C:9]3[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[OH:21])[CH3:17])=[CH:14][C:8]=3[O:7]2)=[O:5])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Solvent: CCO
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)N(Cc1ccccc1)Cc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and benzylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a colorless spongy solid; mp 101; yield 2.0 g; 67%; M+H 600.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[C:21]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])[CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1.N>CN(C=O)C>[CH3:60][C:61]1[CH:67]=[CH:66][C:64]([NH:65][C:17]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:22]=[C:21]([S:23]([F:26])([F:28])([F:27])([F:24])[F:25])[CH:20]=2)=[O:19])=[CH:63][C:62]=1[N:68]1[C:75]2[N:71]([N:72]=[C:73]([C:76]3[CH:77]=[N:78][NH:79][CH:80]=3)[CH:74]=2)[CH:70]=[CH:69]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound from Example 16A (320 mg, 0.74 mmol) was dissolved in 2.3 ml of DMF, HATU (309 mg, 0.81 mmol) and then 4-methylmorpholine (0.32 ml) were added, and the mixture was stirred at RT for 30 min. At −5° C., the compound of Example 7A (103 mg, 0.37 mmol) was then added and the mixture was stirred at RT for 16 h. A few milliliters of concentrated aqueous ammonia solution were then added. The mixture was stirred at RT for 15 min and then extracted with ethyl acetate. The organic phase was washed with conc. sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was purified by preparative HPLC (Method 28). This gave 210 mg (purity 61%, 50% of theory) of the title compound which was used without further purification for the next synthesis step.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1.ClCCl>ClC(Cl)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[S:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CNC(=S)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To a solution of methyl 3-[(methylamino)carbonyl]-5-(5-methylpyridin-2-yl)benzoate (2.90 g, 10.2 mmol) in dichloroethane (20 mL) was added 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (2.27 g, 5.61 mmol) and the mixture heated to 60° C. After 2 h, the reaction was cooled to ambient temperature. Dichloromethane (200 mL) was added, and the mixture washed with 100 mL of saturated aqueous sodium bicarbonate (2×) and brine (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give the title compound (1.9 g). MS 301.0 (M+1).