Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][C:5]1[S:6][C:7]([C:15]([O:17]CC)=[O:16])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1>O.C(O)C.O>[CH2:13]([O:12][C:10]([C:8]1[N:9]=[C:5]([S:4][CH3:3])[S:6][C:7]=1[C:15]([OH:17])=[O:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)c1nc(SC)sc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(SC)sc1C(=O)O
Reaction time: 1 h

Procedure:
At room temperature, a solution of 1.10 g (27.5 mmol) of sodium hydroxide in 10 ml of water was added over a period of one hour to a solution of 7.00 g (25 mmol) of diethyl 2-methylthiothiazole-4,5-dicarboxylate in 100 ml of ethanol/water (2:1). The mixture was stirred for one hour, the solvent mixture was then removed under reduced pressure, the residue was taken up in 100 ml of water, the solution was extracted once with 50 ml of diethyl ether, and the aqueous phase was acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[OH:7][CH:6]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1NC(C(=O)c2ccc(Cl)cc2)CO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1NC(C(O)c2ccc(Cl)cc2)CO1
Reaction time: 1 h

Procedure:
1 g (4.4 mMole) of 4-(p-chlorobenzoyl)-oxazolidin-2-one is dissolved in 50 ml of ethanol, followed by the addition in portions at room temperature of 300 mg (8.0 mMole) of sodium borohydride. After 1 hour, a saturated NH4Cl-solution is added to the reaction solution which is then repeatedly extracted with chloroform. The combined organic phases are dried over Na2SO4 and concentrated. The yellow oil is taken up in ether/hexane. The crystals formed are filtered off under suction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18](O)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C.[NH2:38][C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:40]=1[OH:46]>COCCOC.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:18]2[NH:38][C:39]3[C:40]([OH:46])=[CH:41][CH:42]=[CH:43][C:44]=3[N:45]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: Nc1cccc(O)c1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3nc4cccc(O)c4[nH]3)n2)cc1
Temperature: 170 °C
Yield: 73.7 %

Procedure:
A mixture of 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-carboxylic acid (120 mg, 0.4091 mmol), diethoxyphosphorylformonitrile (73.40 mg, 0.4500 mmol), triethylamine (124.2 mg, 171.1 μL, 1.227 mmol) and 2,3-diaminophenol (50.79 mg, 0.4091 mmol) in DME (5 mL) was heated in the microwave at 170° C. for 1 hour. The mixture was diluted with EtOAc, washed with water and brine and concentrated in vacuo The residue was then dissolved in DCM and triturated with ether to give the desired product as a yellow solid (115 mg, 74% Yield). 1H NMR (400 MHz, DMSO) 3.6 (3H, s), 6.65 (1H, d), 7.1-7.18 (2H, m), 8.0-8.1 (4H, m), 8.6 (2H, d), 8.9 (1H, s), 9.05 (1H, br s), 9.9 (1H, s), 12.9 (1H, b rs) ppm; MS (ES+) 382
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[NH:6][C:7]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:8])([O-])=O>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][O:9][C:7]([NH:6][C:5]3[C:4]([NH2:1])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:8])[CH2:16][CH2:15]2)=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])OCC1CCN(c2ccncc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Yield: 95.1 %

Procedure:
A solution of 2-nitro-N-[[1-(4-pyridyl)piperidin-4-yl]methoxycarbonyl]aniline (7.55 g, 21.2 mmol) and 5% Pd/C (4.00 g) in ethanol was placed under an atmosphere of hydrogen (1 atm). After consumption of the starting material was indicated by tlc (16-20 h), the mixture was filtered through diamotaceous earth using hot ethyl acetate to wash the filter cake. Concentration of the filtrate yielded 6.58 g (96%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.C1C(=O)N([I:21])C(=O)C1>S(O)(C(F)(F)F)(=O)=O>[OH:1][CH2:2][CH2:3][C:4]1[C:13]([I:21])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2cc(CCO)c(I)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (9.00 g, 50.6 mmol) in 100 mL of TfOH was added NIS (12.5 g, 55.6 mmol), then the mixture was stirred at 0° C. for 2 hrs and then poured into ice-water (500 mL). The solution was extracted three times with 500 mL of EtOAc and the combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (EtOAc/Pet Ether=1:5) to give the title compound.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@H:12]([O:13]C(=O)C)[C@@H:11]([CH2:17][O:18]C(=O)C)[O:10][C@H:9]1[N:22]1[N:26]=[C:25]([C:27](=[S:29])[NH2:28])[CH:24]=[N:23]1)(=O)C>CO>[C@@H:9]1([N:22]2[N:26]=[C:25]([C:27](=[S:29])[NH2:28])[CH:24]=[N:23]2)[O:10][C@H:11]([CH2:17][OH:18])[C@@H:12]([OH:13])[C@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc(C(N)=S)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=S)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Sodium methoxide in methanol (60 mg of sodium in 30 ml of methanol) was added to 1.0 g of 9 and the resulting solution was stirred at room temperature for 4 hr. After neutralization with Amberlite IRC 50, the solution was filtered, and the filtrate was evaporated to dryness. Methanol and silica gel (2.5 g) were added to the syrup, and the mixture was evaporated to dryness. The silica gel mixture was added to a dry-packed silica gel column (1 × 18 cm) and the column was eluted with chloroform (0.1 liter), ethylacetate-chloroform (1:1, 0.1 liter) and ethyl acetate (0.4 liter); 20 ml fractions were collected. Fractions 14-28 provided 0.61 g (91%) of 11 as a syrup: nmr (DMSO-d6) δ 5.95 (d, 1, J1',2' 4.0 Hz, 1'--H), 8.32 (s, 1, 5--H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:6]1([CH2:4][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:2]2=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C(N/N=C1\C(=O)N(CC2CCCCC2)c2ccccc21)c1ccccc1
Yield: 71.4 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 7 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 71.4%. 1H NMR (DMSO-d6): δ 1.05-1.09 (m, 2H), 1.18-1.20 (m, 3H), 1.61-1.79 (m, 6H), 3.65 (d, J=7.5 Hz, 2H), 7.22 (t, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.66-7.70 (m, 3H), 7.75 (t, J=7 Hz, 1H), 7.96 (d, J=7 Hz, 2H), 13.97 (br s, 1H). 13C NMR (DMSO-d6): δ 25.68 (CH2), 26.26 (CH2), 30.71 (CH2), 36.40 (CH), 45.90 (CH2), 110.95 (CH), 119.57 (C), 121.19 (CH), 123.67 (CH), 127.87 (CH), 129.68 (CH), 132.19 (CH), 132.44 (C), 133.40 (CH), 137.70 (C), 143.94 (C═N), 161.90 (C═O), 163.42 (C═O). HRMS (ES+) calcd for C22H24N3O2 (M+H+), m/e, 362.1872. found, 362.1863.
Reaction SMILES: P(=O)([O-])[O-].Br[C:6]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1.[NH2:13][NH2:14]>>[Br:12][C:9]1[CH:8]=[N:7][C:6]([NH:13][NH2:14])=[N:11][CH:10]=1
Reactant: NN
Reactant: Brc1cnc(Br)nc1
Agent: O=[PH]([O-])[O-]
Product: NNc1ncc(Br)cn1

Procedure:
The preparation of phosphonates in which the phosphonate is attached by means of a pyrimidinyl group, either directly or with a saturated or unsaturated carbon chain is illustrated above. In this procedure, 2,5-dibromopyrimidine 132.32 (Chem. Lett., 1992, 583) is reacted with hydrazine to afford 5-bromo-2-pyrimidinyl hydrazine 132.33. The preparation of pyrimidinyl hydrazines by the reaction of 2-halopyrimidines with hydrazine is described in J. Med. Chem., 2002, 45, 5397. The product is then reacted with the ketoaldehyde 132.3 to yield the isomeric pyrazoles 132.34 and 132.35. The compound 132.34 is coupled, as described above, with a dialkyl phosphite to afford the phosphonate 132.37; basic hydrolysis then gives the triol 132.36.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2=[O:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CC(c2cccnc2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2cccnc2)O3)c1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 33.7 %

Procedure:
A mixture of 6-bromo-2-(pyridine-3-yl)chroman-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (294 mg, 2 mmol), Cs2CO3 (2 M, 5 mL) and Pd(PPh3)2Cl2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC to give 3-(4-oxo-2-(pyridine-3-yl)chroman-6-yl)benzonitrile (110 mg, 34%). 1H-NMR (MeOD): 2.97-3.02 (d, 1H), 3.25-3.33 (m, 1H), 5.74-5.78 (d, 1H), 7.23 (d, 1H), 7.52 (m, 1H), 7.60-7.64 (m, 2H), 7.70 (d, 1H), 7.90-7.95 (m, 2H), 7.99 (s, 1H), 8.07 (d, 1H), 8.15 (s, 1H), 8.57 (d, 1H), 8.75 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (30 g, 74 mmol) and triethylsilane (50 mL) at 25° C. was added trifluoroacetic acid (15 mL) dropwise. The resulting mixture was stirred at 25° C. for 4 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (15 g, 78%) as a white solid: LC/MS m/e calcd for C20H22BrNO2 (M+H)+: 389.31, observed: 388.0 & 390.0.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O

Procedure:
The product from Example 195B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.34 (d, J=7.1, 1H), 8.08-8.03 (m, 1H), 8.03-7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.56 (d, J=8.6, 2H), 7.44-7.36 (m, 4H), 7.35-7.31 (m, 2H), 3.67 (s, 2H); MS (DCI+) M/Z 519 (M+NH4)+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2>>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:7](=[O:9])[CH2:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COC(=O)CC(=O)C(C)C
Product: CC(C)C(=O)CC(=O)Nc1ccc2[nH]ncc2c1
Temperature: 180 °C

Procedure:
Methyl isobutyrylacetate (3 mL) was mixed with 5-aminoindazole (0.50 g) and heated In a SmithSynthesizer to 180° C. for 300 seconds. The crude mixture was then purified by silica gel chromatography to yield the title compound as a purple solid. 1H NMR (keto- tautomer) (400 MHz, DMSO-D6) δ ppm 12.98 (s, 1H), 10.06 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 3.62 (s, 2H), 2.78 (sept, 1H), 1.06 (d, 6H). MS m/z 246 (M+1)+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].[CH3:20][C:21]([N+:27]([O-:29])=[O:28])([CH3:26])[CH2:22][CH2:23][CH2:24]I>C(O)C>[C:5]([NH:8][C:9]([CH2:24][CH2:23][CH2:22][C:21]([CH3:26])([N+:27]([O-:29])=[O:28])[CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCC(C)(C)[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Yield: 83.4 %

Procedure:
20% Sodium ethoxide (3.74 g, 11 mmol) and diethyl 2-acetamidomalonate (2.39 g, 11 mmol) were dissolved in ethanol (10 ml). A solution of 4-methyl-4-nitropentyl iodide (2.57 g, 10 mmol) in ethanol (8 ml) was added and the mixture was refluxed under heating for 5 h. Ethanol was evaporated by concentration under reduced pressure and ethyl acetate (50 ml) was added. The mixture was washed with water (20 ml) and saturated brine (20 ml). Ethyl acetate was evaporated by concentration under reduced pressure and the residue was purified by silica gel column chromatography to give the objective compound (2.89 g, yield 83.4%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>O>[N:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Brc1ccncc1
Solvent: O
Product: c1cc(N2CCNCC2)ccn1
Temperature: 145 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To piperazine (3.6 g) dissolved at 110° C. was added 4-bromopyridine (1.0 g) and the mixture was stirred at 140-150° C. for 1 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (0.64 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.CN1CCOCC1.Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][NH:35][C:5](=[O:7])[C@@H:4]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:3][CH:2]([CH3:1])[CH3:15])=[CH:27][CH:26]=1
Reactant: CC(C)C[C@H](NC1CCOCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)C[C@H](NC1CCOCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A suspension of (S)-4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid (430 mg, 2.00 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (597 mg, 2.00 mmol) in dry DMF (10 mL) was treated with Triton® B (1.82 mL, 4.00 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.760 g, 2.00 mmol) was then added. After stirring at 0° C. for 30 minutes, was added, the cooling bath was then removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5) to give 300 mg (39%) of the pure titled compound as a clear oil. APCI-MS m/z 459.4 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:54][C@@H:55]2[CH2:59][NH:58][C@H:57]([C:60]([NH:62][C@:63]3([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:65][C@H:64]3[CH:66]=[CH2:67])=[O:61])[CH2:56]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([O:54][C@@H:55]2[CH2:59][N:58]([C:34](=[O:36])[C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C@H:57]([C:60]([NH:62][C@:63]3([C:68]([O:70][CH2:71][CH3:72])=[O:69])[CH2:65][C@H:64]3[CH:66]=[CH2:67])=[O:61])[CH2:56]2)(=[O:52])=[O:53])=[CH:47][CH:46]=1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1)C(=O)OCC
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](OS(=O)(=O)c2ccc(Br)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
HATU (27.3 g) was added to the solution of (2S)-2-[(tert-butoxycarbonyl)amino]non-8-enoic acid (19.5 g) in DMF (100 ml) and the solution was stirred 15 minutes. The reaction mixture was cooled to 0° C. Then, the amine from Step 3 (31.8 g) in DMF (200 ml) (cooled to 0° C.) was added followed by DIPEA (11.40 ml). The solution was stirred at 0° C. for 1 hour. Hydrochloric acid (1M) was added and the mixture was extracted with diethyl ether (3×). The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (40.2 g) as a white foam. LRMS (ES+) m/z 762.2 (M+Na)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 409.14 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CCCCBr
Reactant: Oc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)CCCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A 500 ml 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 12.86 (100 mmol) 2-chloro phenol, 23.49 g (110 mmol) ethyl 5-bromovalerate, 16.60 g (120 mmol) potassium carbonate and 300 mL of 2-butanone. The slurry heated to reflux. After stirring for 20 hr at reflux (completeness confirmed by HPLC), the reaction mixture was cooled to 25° C., filtered and concentrated. The residue was taken up in of water (300 ml) and treated with 100 ml (200 mmol) 2N aqueous sodium hydroxide. This suspension was heated to reflux for 2 hours until it turned to a solution. The solution was cooled to 25° C. Ice was added to further cool to 0° C. The yellow solution was acidified with aqueous 105 ml 2N hydrochloric acid. The resulting white solid was isolated by filtration washing with water twice then hexanes twice to yield 22.24 g (97%) of the desired product, Mp 71-72° C. Combustion analysis: Found: C, 57.66%; H, 5.82%, Cl, 15.5%; Calculated: C, 57.78%; H, 5.73%; Cl, 15.5%; 1H NMR (d6-DMSO): δ 12.1, broad s, 1H (COOH); δ 7.40, dd, 1H (aryl H); δ 7.25, m, 1H (aryl H); δ 7.10, dd, 1H (aryl H); δ 6.9, m, 1H (aryl A); δ 4.0, t, 2H (CH2 α ArO); δ 2.3, t, 2H (CH2 α COOH); δ 1.7, m, 4H (rest of CH2's).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC

Procedure:
A solution of 5.6 g (15 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boiled under reflux for 4 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The crude product is recrystallized from ethanol, yielding the title compound in the form of yellow crystals, m.p. 178°, FAB-MS: 377 [M+ +H].