Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=O.[Cl-].[OH:31][NH3+:32].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[N:32][OH:31]
Reactant: [NH3+]O
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
27 g (65.1 mmol) of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.5 g (65.1 mmol) of hydroxylammonium chloride and 12.9 g (163 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 13.5 g of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone oxime as a beige solid with a melting point of 76-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.88 (t, 3H), 1.20-1.40 (m, 24H), 1.40-1.50 (m, 2H), 1.75-1.84 (m, 2H), 3.96-4.02 (m, 2H), 6.89(E)/6.95(Z) (d, 2H), 7.43(E)/7.52(Z) (d, 2H), 8.28(Z)/8.43(E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=7:3.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH3:9].O.C(O)(=O)C.[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:20]([CH:7]=[CH:8][CH3:9])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CNCC(C)C
Reactant: CCC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: O
Product: CC=CN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.2 g) was added dropwise propionaldehyde (16.4 g) at 0-10° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1.5 hours. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5° C. and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5° C., and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (42.5 g, yield: 81%, purity: 95.3%) as a colorless oil.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:5]2[C:4]([CH2:3][OH:2])=[C:8]([CH3:9])[N:7]=[CH:6]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1[nH]cnc1CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
To a solution of 19 g of 4-hydroxymethyl-5-methylimidazole hydrochloride in 350 ml of dimethylformamide was added 36 ml of triethylamine followed in 10 minutes by the addition of 35 g of trityl chloride. A water bath was used to cool the reaction mixture such that it did not rise above 36° C. After stirring at room temperature for 4 hours, the mixture was poured into 1 liter of water and ice. The resulting precipitate was filtered and washed with acetone (2×250 ml) to give 22 g of product.
Reaction SMILES: N[C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](CSC1C=C(C)N3N=CC=C3N=1)=[C:7]2[C:11]([OH:13])=[O:12].O.C(N(CC)CC)C>C(#N)C>[O:10]=[C:9]1[N:8]2[CH:3]([S:4][CH2:5][CH:6]=[C:7]2[C:11]([OH:13])=[O:12])[CH2:2]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2ccnn12
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCSC2CC(=O)N12
Reaction time: 1 h

Procedure:
1.00 g of (6R,7R)-7-amino-3-[[(7-methylpyrazolo-[1,5-a]pyrimidin -5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was brought into solution in 5 ml of acetonitrile and 5 ml of water with 0.37 ml of triethylamine. The solution was treated with 1.0 g of 2-amino-4-thiazolethioglyoxylic acid S-(2-benzothiazolyl) ester and stirred at 20° for 1 hour. The reaction mixture was partitioned between water and ethyl acetate and the aqueous phase was chromatographed on Optiup (C12) (Antec AG, CH-Bennwil) with a gradient of 0% to 10% acetonitrile in water. The product fractions Were concentrated to 10 ml and adjusted to pH 2.2 with HCl. The precipitate was filtered off under suction. There was obtained (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[7-methylpyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br.O>CO>[Br:13][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1OC
Solvent: O
Solvent: CO
Product: COc1cc(Br)c(C=O)cc1OC
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 500 g of 3,4-dimethoxybenzaldehyde in 2.5 L of methanol was added dropwise 529 g of bromine at room temperature (under cooling, if necessary) over 1 hour, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added dropwise 2.5 L of water, and the crystals were precipitated. To the crystal suspension was added 20% aqueous sodium hydroxide solution at room temperature to adjust it to pH about 9 to 10, and then cooled. The precipitated crystals were collected by filtration and washed with water, and then dried at 50° C. for 12 hours to give 718.78 g of 6-bromo-3,4-dimethoxybenzaldehyde (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:26]2=[O:40])[CH2:12][CH2:13][CH2:14][N:15]([CH3:24])[S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C.C(O[C:48]1(O[Si](C)(C)C)[CH2:50][CH2:49]1)C.C([BH3-])#N.[Na+]>CO>[CH:48]1([N:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:32]=3[CH2:33][N:25]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH2:13][CH2:14][N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:26]4=[O:40])[CH2:39][CH2:38]2)[CH2:50][CH2:49]1
Reactant: COc1ccc([C@@H](CCCN(C)S(=O)(=O)c2cccs2)N2Cc3c(cccc3N3CCNCC3)C2=O)cc1OC
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc([C@@H](CCCN(C)S(=O)(=O)c2cccs2)N2Cc3c(cccc3N3CCN(C4CC4)CC3)C2=O)cc1OC
Temperature: 25 °C
Yield: 22.6 %

Procedure:
According to the method of M. L. Gillaspy, B. A. Lefke, W. A. Hada, D. J. Hoover, Tetrahedron Letters 1995, 7399-7402, Cpd 30 (50 mg, 0.085 mmol), acetic acid (0.050 mL, 0.87 mmol), 3 Å molecular sieves (230 mg), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.102 mL, 0.51 mmol) were combined in methanol (4 mL) at rt. Sodium cyanoborohydride (24 mg, 0.38 mmol) was added and the reaction mixture was heated at reflux overnight, cooled to RT, filtered, and concentrated. The residue was dissolved in EtOAc (25 mL), washed with 2 N sodium hydroxide solution (2×10 mL) and brine (2×10 mL), dried (Na2SO4), concentrated, and purified by reversed phase HPLC [Phenomenex, Kromasil C18, 10μ, 110 Å, 250×50 mm, gradient elution with 20-90% acetonitrile (0.16% TFA) in water (0.2% TFA)] to yield Cpd 7 (12 mg, 19%) as a TFA salt. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=7.4 Hz, 1H), 7.59 (d, J=4 Hz, 1H), 7.52 (d, J=4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.13 (t, J=4 Hz, 1H), 6.99 (br d, J=8.2 Hz, 1H), 6.92 (br s, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.56 (br t, J=7.5 Hz, 1H), 4.34 (d, J=17 Hz, 1H), 3.93 (buried d, J=17 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.7-2.9 (m, 11H), 2.66 (s, 3H), 2.5-2.0 (m, 6H), 1.7 (m, 2H); LC/MS (ES+) m/z 625.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[N:18]=2)[N:6]=1)=[O:4].[Li+].[OH-].[ClH:30]>[Cl-].[Na+].O>[ClH:30].[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5]([C:3]([OH:4])=[O:2])=[N:6]3)[S:15][CH:16]=2)=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1nn(-c2nc(-c3ccc(C(C)C)cc3)cs2)c2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CC(C)c1ccc(-c2csc(-n3nc(C(=O)O)c4ccccc43)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the 1-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-1H-indazole-3-carboxylic acid methyl ester (150 mg, 0.22 mmol) was added LiOH (5 mL; 2N LiOH-MeOH-THF=1:1:4) and stirred at room temperature for 4 h before acidifying with 1N HCl. Brine was added and the aqueous was extracted with DCM (3×15 ml). Combined extracts were dried over Na2SO4, concentrated and purified on silica gel column to provide 1-[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-1H-indazole-3-carboxylic acid hydrochloride salt (48 mg). LCMS m/z: 365 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccccc2OC)c1C(=O)OC
Yield: 77 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-methoxyaniline (0.38 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.75 g of the product at 75:25 hexanes-ethyl acetate, in 77% yield: 1H NMR (CDCl3) δ 3.88 (s, 9H), 6.89-7.00 (m, 3H), 7.14 (d, J=7.0 Hz, 1H), 7.27-7.34 (m, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.99 (br, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 31 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 93.7%) was a white foam: [α]23589=−23.24° (c=0.37, chloroform); EI-HRMS m/e calcd for C20H22Cl2N4O4S (M+H)+ 485.0812, found 485.0822.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:6]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(C(=O)N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a suspension of 2-fluoro-3-methoxy-4-nitrobenzoic acid (180 mg, 0.97 mmol) in DCM (8 mL) was added morpholine (0.17 mL. 1.9 mmol), DIEA (0.25 mL) and HBTU (0.4 g, 1.05 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with water and extracted with DCM (3×). The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography to give (2-fluoro-3-methoxy-4-nitrophenyl)(morpholino)methanone (0.20 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:11][OH:12])=[CH:8][N:9]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]([Cl:19])=[N:11][OH:12])=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncc(C(Cl)=NO)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of Example 30C (12 g, 42 mmol) in N,N-dimethyl formamide (80 mL) was added N-chlorosuccinimide (5.6 g, 42 mmol). The mixture was stirred at ambient temperature for 16 hours, water (1000 mL) was added and the resulting suspension was filtered. The solids were dried in a vacuum oven to provide 12.8 g of the title compound (95%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.04 (dd, J=8.82, 2.94 Hz, 1H) 7.26 (d, J=2.94 Hz, 1H) 7.54 (d, J=9.19 Hz, 1H) 7.66 (s, 1H) 12.48 (s, 1H); MS (ESI) m/z 319.9 (M+H)+.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[C@:5]([NH2:17])([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[F:16])[CH3:6].[CH3:21][NH:22][C:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=S>>[C:28]([O:27][C:26](=[O:32])[NH:25][C:23]1[N:22]([CH3:21])[C:3](=[O:20])[C:4]([CH3:18])([CH3:19])[C@:5]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])([CH3:6])[N:17]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cc([N+](=O)[O-])ccc1F
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-5-nitro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-5-nitro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as pale yellow oil. MS (ESI): m/z=407.3 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: O=C1CCCN1CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCCC1=O

Procedure:
The 1-(2-hydroxyethyl)-2-pyrrolidinone (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:3]2[C:2]([OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][CH:5]=1)[CH3:21]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Oc1cccc2[nH]ccc12
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c[nH]c2cccc(O)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-hydroxy-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Br)cc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
4-Methoxybenzylchloride (0.6 mL, 4.4 mmol) was added to a mixture of 2,4-dibromo-phenol (1 g, 4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in DMF (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hr. After adding cesium carbonate (1.3 g, 4 mmol), the resulting mixture was stirred at 90° C. for 2 hrs. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc twice. The combined EtOAc extracts were washed with a mixture of water and brine several times, then concentrated to afford 1.45 g (98% yield) of 2,4-dibromo-1-(4-methoxy-benzyloxy)-benzene as a light yellow oil, which was used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:40]=[CH:39][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([F:38])[CH:26]=4)=[CH:21][C:20]=3[O:41][CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[ClH:45].C(OCC)(=O)C>CO.O1CCCC1.C(OCC)(=O)C>[ClH:45].[ClH:45].[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:40]=[CH:39][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:38])[CH:26]=4)=[CH:21][C:20]=3[O:41][CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CNc2ccc(CCC(=O)O)c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-methoxybenzyl}amino)-2-fluorophenyl]propanoate (0.57 g, 1.01 mmol) in a mixture of methanol (4.0 mL) and tetrahydrofuran (8.0 mL) was added 1 N aqueous sodium hydroxide solution (2.02 mL, 2.02 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and 4 N hydrogen chloride/ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried to give the title compound (0.48 g, yield 77%) as colorless crystals.
Reaction SMILES: [CH2:1]([P:3]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])(=O)[O:4][CH2:5][CH3:6])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>>[CH2:1]([P:3]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])(=[S:32])[O:4][CH2:5][CH3:6])[CH3:2]
Reactant: CCOP(=O)(CC)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CCOP(=S)(CC)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of ethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by prep. TLC to give O-ethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinothioate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8](C#N)[C:9]2[CH:10]=C[C:12]([F:17])=[C:13]([CH:16]=2)C#N)=[C:4]([CH2:20][CH3:21])[CH:3]=1.Cl.O.[CH3:24][C:25]([OH:27])=[O:26]>O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:16]=[CH:13][C:12]([F:17])=[C:24]([CH:10]=2)[C:25]([OH:27])=[O:26])=[C:4]([CH2:20][CH3:21])[CH:3]=1
Reactant: CCc1cc(Cl)nnc1C(C#N)c1ccc(F)c(C#N)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)nnc1Cc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of Example 1, A2 (1 eq) in AcOH:conc.HCl:H2O (1:10:1, 0.065 M) was heated at reflux overnight. The reaction mixture was then cooled down to RT and diluted with water/EtOAc. The organic phase was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. MS (ES) C14H12ClFN2O2 required: 294/296. found: 295/297 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.Cl.[Sn]>C(O)(=O)C>[Cl:12][C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: Clc1cc2ccccc2cn1
Temperature: 57.5 °C

Procedure:
The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60° C. for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).