Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=3[CH3:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:42]([O:44][P:45]([CH2:50]OS(C(F)(F)F)(=O)=O)([O:47][CH2:48][CH3:49])=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][P:45]([CH2:50][O:31][C:27]1[CH:26]=[C:25]([CH3:32])[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])=[NH:9])[S:11][C:12]=3[S:33][CH3:34])(=[O:17])=[O:16])[CH:19]=2)=[C:29]([CH3:30])[CH:28]=1)(=[O:46])[O:47][CH2:48][CH3:49])[CH3:43]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1)OCC
Reaction time: 18 h
Yield: 33 %

Procedure:
To a flask containing {[4-(4′-hydroxy-2′,6′-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 224: step b) 233 mg, 0.42 mmol), Cs2CO3 (137 mg, 0.42 mmol), DMF (2 mL), and trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (200 mg, 0.67 mmol, (Xu, Y. et al J. Org. Chem. 61, 7697 (1996); Phillion, D. et al Tetrahedron Lett. 27, 1477 (1986)) were added and heated to 50 C. This mixture was heated and stirred for 18 h under an Ar atmosphere. DMF was removed under vacuum and the residue was taken in EtOAc and washed with water and saturated NaCl. The EtOAc layer was separated dried over Na2SO4 and evaporated under vacuum to give an oil. This was purified by preparative thin-layer chromatography (EtOAc/Hexane) to give 94 mg (33%) of {3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxymethyl}-phosphonic acid diethyl ester as a white solid. This solid was dissolved in dichloromethane (2 mL), and cooled in an ice bath. To this iodotrimethylsilane (Aldrich Chemical Company, 60 μL) was added and the mixture was stirred for 1 h at which time the dichloromethane was removed and the residue was taken in MeOH and treated with 6N HCl. This mixture was stirred for 3 h and the solvents were removed under high vacuum. To this residue a 50% solution of TFA in dichloromethane was added and the mixture was stirred for 1 h. TFA and dichloromethane were removed under vacuum and the residue was purified by preparative HPLC (Rev. Phase acetonitrile/water) which yielded the title compound as a white solid (30 mg, 33%). 1H-NMR (CD3OD): δ 7.8–7.7 (m, 2H), 7.62 (s, 1H), 7.5–7.3 (m, 2H), 6.7 (s, 2H), 3.77 (d, 2H, J=9.8 Hz), 2.44 (s, 3H), 1.74 (s, 6H). ESI-MS (m/z): Calcd. for C21H23N2O6PS3: 527.1 (M+H); found: 527.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]2.C[Si](Cl)(C)C>C(O)CCC>[F:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[N:42]([CH3:46])[C:41](=[O:47])[CH2:40][CH2:39]4)[N:3]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(Nc4ccc(F)cc4)c4c(-c5ccncc5)c[nH]c4n3)ccc21

Procedure:
A solution of 2-chloro-N-(4-fluorophenyl)-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.062 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (25 mg, 0.14 mmol) and trimethylsilyl chloride (0.100 mL, 0.790 mmol) in nBuOH (1 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 480.5 (M+H); UV 204.7, 281.7, 314.3 nm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCOc1ccc(Nc2ccccc2CC(=O)O)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitro-4-ethoxyaniline to yield 2-[(2-nitro-4-ethoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Na].Br[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>C(O)C>[ClH:1].[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Brc1ccc(N2CCC2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Azetidine hydrochloride (3.0 g, 32.1 mmol) was added to a solution of sodium (0.73 g, 31.7 mmol) in ethanol (25 ml) and the solution stirred vigorously for an hour. 2,5-Dibromopyridine (5.0 g, 21.1 mmol) was then added and the reaction mixture heated at 100° C. for 10 hours in a sealed vessel, and then at 120° C. for a further 10 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated, the aqueous phase was extracted with ethyl acetate (3×), and the combined organic extracts washed with brine, dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by medium pressure column chromatography on silica gel, using dichloromethane:pentane (66:34) as eluant to give the tile compound, (900 mg, 17%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][NH2:10]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN
Solvent: CO
Product: CNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
2,4-Dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M monomethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N-monomethylamino)pyrimidine (106b, 128 mg, 27%) as a yellow solid.
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[N:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[C:18]=1O[Si](C(C)(C)C)(C)C.[N:38]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24]([N:27]([CH3:28])[CH3:29])(=[O:25])=[O:26])[CH:18]=1)=[NH:38]
Reactant: N#CN
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CNC(=N)N
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1cc(NC(=N)N(C#N)c2ccccc2Cl)ccc1Cl
Yield: 50 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-(2-chlorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]carbodiimide (300 mg, 0.6 mmol), cyanamide (100 mg, 2.4 mmol) and N,N-diisopropylethylamine (94 mg, 0.72 mmol) were reacted, followed by desilylation with Cesium fluoride (110 mg, 0.72 mmol) to form the desired product (129 mg, 50%). EI-MS m/z 428.0 (M+). 1H NMR (DMSO-d6) δ 2.86 (s, 6H), 7.2 (d, 1H), 7.32 (t, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 7.51 (d, 1H), 7.57 (d, 1H), 8.98 (s, 1H), 9.18 (s, 1H), 10.51 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:20].[Mg+2].C(=O)(O)[O-].[Na+]>CO.O>[CH3:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[O:20][C:3]1=[O:9]
Reactant: CC1CCCC(C)C1=O
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCCC(C)C(=O)O1
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A 250 mL round bottom flask was charged with 2,6-dimethylcyclohexanone (2.162 mL, 2.0 g, 15.85 mmol) and 126 mL of a 1:1 methanol/water mixture. The solution stirred as magnesium monoperoxyphthalate hexahydrate (MMPP, 15.68 g, 31.7 mmol) and sodium bicarbonate (2.66 g, 31.7 mmol) were added. The reaction proceeded overnight at room temperature with stirring. The following day the crude product was extracted into ethyl acetate, washed sequentially with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate before concentrating in vacuo to give 1.07 g (47.5% yield) of 3,7-dimethyloxepan-2-one (61) as a clear, colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.C1(C[N:26]2[CH:30]=[C:29]([C:31]3S[C:33]([C:37](O)=O)=[C:34](C)[N:35]=3)N=N2)CC1.N1C=CC=C(CN)C=1>>[CH:2]1([CH2:1][N:8]2[CH:12]=[C:11]([C:13]3[S:14][C:15]([C:19]([NH:26][CH2:30][C:29]4[CH:31]=[N:35][CH:34]=[CH:33][CH:37]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[N:10]=[N:9]2)[CH2:7][CH2:6]1
Reactant: Cc1nc(-c2cn(CC3CC3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(CC3CC3)nn2)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 57% yield: mp 140-141° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.73-8.48 (m, 2H), 8.24 (s, 1H), 7.76-7.66 (m, 1H), 7.39-7.19 (m, 1H), 6.71 (br s, 1H), 4.62 (d, J=5.3 Hz, 2H), 4.26 (d, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.39-1.23 (m, 1H), 0.81-0.66 (m, 2H), 0.53-0.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.3, 157.3, 149.2, 148.9, 143.9, 142.5, 135.8, 133.8, 124.1, 121.2, 55.5, 41.6, 17.3, 10.8, 4.4; MS (ES+) m/z 355.3 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.[C:16]([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.Cl[C:29]1([Pb+3])[C:34]([CH3:35])=[CH:33][C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH2:30]1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:16][C:30]1[CH:31]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[C:34]([CH3:35])[C:29]=1[CH:4]1[C:5](=[O:10])[C@H:6]2[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]2)[C:3]1=[O:11]
Reactant: CC1=CC(c2ccccc2)=CCC1(Cl)[Pb+3]
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 32.7 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.298 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Chloro-3-methylbiphen-4-yllead triacetate (0.836 g, 1.428 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(3,5-dimethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.142 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:9][O:10][C:11]1[C:12](Br)=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:25])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1CCC[C@H:33]1C(O)=O.[Cu]C#N>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:9][O:10][C:11]1[C:12]([C:33]#[N:32])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([CH3:25])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Agent: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](COc1cc2c(cc1C#N)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 12 h
Yield: 16.7 %

Procedure:
To a mixture of tert-butyl((2S)-1-((9-bromo-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.203 mmol) (prepared as described in Example 21, Part A) and L-proline (23.43 mg, 0.203 mmol) in DMF (2 mL) was added copper(I) cyanide (36.5 mg, 0.407 mmol). Argon gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under argon atmosphere at 120° C. for 12 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified via silica gel chromatography (pet ether: ethyl acetate mobile phase) to afford tert-butyl((2S)-1-((9-cyano-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (15 mg, 0.034 mmol, 17% yield). LCMS (ESI) m/e 438.2 [(M+H)+, calcd for C25H32N3O4438.2] LC/MS retention time (method D): tR=1.81 min.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH3:1][N+:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5]
Reactant: CN(CCO)CCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C[N+](C)(CCO)CCO
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Dimethyl di (βhydroxyethyl) ammonium para-toluene sulfonate (A) is prepared from methyl diethanolamine being added slowly and with stirring to methyl para-toluene sulfonate. Product (A) is rinsed and dried under slightly lowered pressure.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].C(OC1CC(=O)N(CC(N(C(C)C)C2C=CC=CC=2)=O)C2C=CC=CC=2N=1)C.[F:63]C1C=CC=CC=1C(NN)=O>>[F:63][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:11]1[N:10]2[C:14]([CH2:15][C:16](=[O:17])[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=32)=[N:13][N:12]=1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: NNC(=O)c1ccccc1F
Agent: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3F)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Preparation 7(A), 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (200 mg, 0.527 mmol) is reacted with 2-fluorobenzhydrazide (81 mg, 0.527 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 3% MeOH in CH2Cl2) provided 180.2 mg of 2-(1-(2-fluorophenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 7.73 (m, 1), 7.64 (d, 1), 7.91-7.18 (m, 8), 7.12-7.00 (m, 2), 6.83 (d, 1), 4.96 (m, 1), 4.23 (d, 1), 4.06 (d, 1), 3.80 (d, 1), 3.58 (d, 1), 1.09 (d, 6); MS 470.3 (M+1)
Reaction SMILES: [CH3:1][O:2]C(OC)CNC1C=CC(F)=CC=1.[CH3:15][O:16][CH:17]([O:31][CH3:32])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.[NH2:33][C:34]1[S:35][C:36]([C:40]([NH:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:41])=[C:37]([CH3:39])[N:38]=1>>[CH3:32][O:31][CH:17]([O:16][CH3:15])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=1)[C:1](=[O:2])[NH:33][C:34]1[S:35][C:36]([C:40]([NH:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:41])=[C:37]([CH3:39])[N:38]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1cccnc1
Reactant: COC(CNCc1ccc(C(F)(F)F)cc1)OC
Reactant: COC(CNc1ccc(F)cc1)OC
Product: COC(CN(Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2cccnc2)s1)OC
Yield: 52 %

Procedure:
Following the procedure as described in step B of Preparation 2, making variations as required to replace N-(2,2-dimethoxyethyl)-4-fluoroaniline with 2,2-dimethoxy-N-(4-(trifluoromethyl)benzyl)ethanamine to react with 2-amino-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, 2-(3-(2,2-dimethoxyethyl)-3-(4-(trifluoromethyl)benzyl)ureido)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide was obtained in 52% yield: 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=1.5 Hz, 1H), 8.39-8.37 (m, 1H), 7.76-7.60 (m, 3H), 7.45 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.19-7.15 (m, 1H), 4.71-4.40 (m, 5H), 3.40 (d, J=4.8 Hz, 2H), 3.27 (s, 6H), 2.51 (s, 314); MS (ES+) m/z 538.5 (M+1).
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][N:12]=[C:11](F)[CH:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:17]([NH:24][C:11]1[CH:10]=[C:9]([NH2:8])[C:14]([F:15])=[CH:13][N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(F)ncc1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: Nc1cc(NCc2ccccc2)ncc1F
Yield: 58.4 %

Procedure:
To 1 ml of N-methylpyrrolidone was added 410 mg of 4-amino-2,5-difluoropyridine together with 930 mg of benzylamine, and the mixture was allowed to react in nitrogen atmosphere at 150° C. for 3 days and allowed to cool. After adding 30 ml of chloroform, the mixture was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 15 g; eluent: chloroform: methanol, 1:0 and then, 50:1) to obtain 400 mg of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH:21]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([P:15](=[O:18])([OH:17])[OH:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39]([O:45][CH:46](I)[CH3:47])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(#N)C.C(Cl)Cl>[OH:18][P:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:10][CH:11]=1)([O:17][CH:46]([O:45][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:47])=[O:16]
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(O)OC(C)OC(=O)C(C)(C)C)cc2)cc(C(=O)Nc2nccs2)c1
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
A mixture of {-4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl-)phenoxy]-phenyl}-phosphonic acid (250 mg, 0.58 mmol) and DIEA (0.193 mL, 1.16 mmol) in 6 mL of acetonitrile was stirred for 15 min and then 1-iodoethyl pivalate (177 mg, 0.69 mmol) was added. The resulting mixture was stirred for 2 h at rt, then diluted with CH2Cl2, washed with 1 M aqueous NaHSO4, dried (MgSO4) and evaporated. The residue was dissolved in 3:1 acetonitrile/water and subjected to MPLC purification through a 25 g C18 column eluting with % acetonitrile in water (time): 15-50 (15 min). Lyophilization of the eluent containing the desired product provided 31 mg (10%) of the title compound as an amorphous solid: 1H NMR (500 MHz, DMSO-d6): δ 0.91 (s, 9H), 1.29 (d, 6H, J=6 Hz), 1.30 (d, 3H, J=6 Hz), 4.73 (septet, 1H, J=6 Hz), 6.34 (br s, 1H), 6.75 (s, 1H), 7.01 (d, 2H, 1=7 Hz), 7.24 (s, 1H), 7.28 (d, 1H, J=3 Hz), 7.45 (s, 1H), 7.56 (d, 1H, J=3 Hz), 7.63 (br s, 2H), 12.61 (br s, 1H); LCMS (m/z): 563.4 [C26H31N2O8PS+H]+. Anal. calcd. for (C26H31N2O8PS+1H2O): C, 53.79; H, 5.73; N, 4.82. Found: C, 52.93; 11, 5.93; N, 5.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc(Br)cc1
Product: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-bromoaniline (67 mg, 0.39 mmol). The title compound was obtained as a solid (55 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.63 (1H, s), 9.01 (2H, s), 8.71 (1H, s), 7.63 (2H, m), 7.56 (2H, m). MS m/z: 502.01, 503.94, 505.92 [M+H]+.
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-:37])=[O:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:45]1[C:50]([F:51])=[C:49]([F:52])[C:48](OC(C(F)(F)F)=O)=[C:47]([F:60])[C:46]=1[F:61]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:45]2[C:50]([F:51])=[C:49]([F:52])[CH:48]=[C:47]([F:60])[C:46]=2[F:61])=[O:36])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:11]=1
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Reactant: COc1ccc(C(NCCCCCC(=O)[O-])(c2ccccc2)c2ccccc2)cc1
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The acid 6 obtained as described above (2.2 g, 4.4 mmol) was dissolved in anhydrous CH2Cl2 and treated with 1 ml of triethylamine followed by 0.8 ml of 2,3,5,6-tetrafluorophenyltrifluoroacetate. After being kept at room temperature for 30 min, the reaction was concentrated to an oil (crude 7), which then was re-suspended in 20% ethyl acetate/80%hexane and applied to a silica gel column. Elution with 15% ethyl acetate/85% hexane and concentration of the pure product fractions afforded 2.0 g (82%) of the TFP ester (7) as a colorless, viscous oil.