Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:34])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.58 mmol) produced in Example 12(v) was dissolved in pyridine (3.0 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.88 mmol) was added, and the mixture was stirred at 70° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed successively with water (10 mL) and saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=10/90→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 39%) as a colorless powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:18][C:19]2[C:20]([CH3:26])=[N:21][N:22]([CH3:25])[C:23]=2[CH3:24])[CH:17]=1)[C:13]#[N:14].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([CH3:26])[C:19]=1[O:18][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Cl:9])[CH:17]=1)[C:13]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C)c(C)c1Oc1cc(Cl)cc(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nn(C)c(CBr)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-Bromosuccinimide (340 mg, 1.90 mmol) was added to a stirred solution of the pyrazole of Example 112 (500 mg, 1.90 mmol) in carbon tetrachloride (10 ml) and azobisisobutyronitrile (20 mg) at room temperature under nitrogen. The reaction was heated under reflux for 1 hour, cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (340 mg) as a white solid, m.p. 76-78° C.
Reaction SMILES: [CH:1]#[C:2][CH2:3]C(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)CC1N=C2C(N)=NC(N)=NC2=NC=1.[H-].[Na+].[CH3:38][O:39][C:40](=[O:52])[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1.C(Br)C#C>C1COCC1.O.C(O)(=O)C>[CH3:38][O:39][C:40](=[O:52])[CH:41]([CH2:3][C:2]#[CH:1])[C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Reactant: C#CCC(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CCC(C(=O)OC)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
FIG. 1 shows a synthetic scheme useful in preparing 10-propargyl-10-deazaaminopterin. A mixture of 60% NaH in oil dispersion (1.06 g, 26.5 mmol) in 18 mL of sieve-dried THF was cooled to 0° C. The cold mixture was treated with a solution of homoterephthalic acid dimethyl ester (5.0 g, 24 mmol. compound 1 in FIG. 1) in dry THF (7 mL), and the mixture was stirred for 1 hour at 0° C. Propargyl bromide (26.4 mmol) was added, and the mixture was stirred at 0° C. for an additional 1 hour, and then at room temperature for 16 hours. The resulting mixture was treated with 2.4 mL of 50% acetic acid and then poured into 240 mL of water. The mixture was extracted with ether (2×150 mL). The ether extracts were combined, dried over Na2SO4, and concentrated to an orange-yellow oil. Chromatography on silica gel (600 mL of 230-400 mesh) with elution by cyclohexane-EtOAc (8:1) gave the product α-propargylhomoterephthalic acid dimethyl ester (compound 2) as a white solid (4.66) which appeared by TLC (cyclohexane-EtOAc, 3:1) to be homogeneous. Mass spectral data on this product, however, showed it to be a mixture of the desired product 2, and the di-propargylated compound. No starting material 1 was detected. HPLC shows the ratio of mono- to di-propargylated products to be about 3:1. Since the dipropargylated product, unlike compound 1, cannot produce an unwanted coproduct in the next step of the reaction, this material was suitable for conversion to compound 3. Absence of starting compound 1 in the product used to proceed in the synthesis is very important in order to avoid the sequential formation of 10-dAM during the transformations lading to the final product, because complete removal from 10-dAM from 10-propargyl-10-deazaaminopterin is very difficult.
Reaction SMILES: [N:1]1([C:5](=[O:7])[CH3:6])[CH:4]=[CH:3][CH2:2]1.[CH:8](=[N:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC1C=CC=CC=1N>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([CH2:2][NH:1][C:5](=[O:7])[CH3:6])=[CH:4]2
Reactant: CC(=O)N1C=CC1
Reactant: Fc1ccccc1/N=C/c1ccccc1
Agent: Nc1ccccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: CC#N
Product: CC(=O)NCc1cc2cccc(F)c2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 1-(azet-1(2H)-yl)ethanone (22 mg, 227 μmol, eq), (E)-N-benzylidene-2-fluorobenzenamine (45 mg, 227 μmol, 1 eq), 2-fluorobenzenamine (22 μl, 227 μmol, 1 eq), and yttrium trifluoromethanesulfonate (6 mg, 11 μmol, 0.05 eq) in 9 mL of acetonitrile. The reaction was stirred at rt overnight. The reaction was heated to 90° C. for 5 h. The reaction was cooled to rt and the solvent was removed under vacuum. The residue was dissolved in 20 mL of DCM and washed with 1×5 mL of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (7:3 hexanes:ethyl acetate) afforded N-((8-fluoro-2-phenylquinolin-3-yl)methyl)acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 1H), 7.60 (d, J=7.83, 1H), 7.50 (m, 2H), 7.45 (m, 4H), 7.37 (ddd, J=10.6, 7.8, 1.6 Hz, 1H), 5.92 (br t, J=5.9 Hz, 1H), 4.55 (d, J=6.3 Hz, 2H), 1.96 (s, 3H). Mass Spectrum (ESI) m/e=295.0 (M+1).
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].CN1CCCC1=O.[P:39](Cl)(Cl)[Cl:40]>C1(C)C=CC=CC=1>[Cl:40][P:39]1[O:16][C:3]2[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:7][C:2]=2[CH2:1][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[O:31]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 25.0 g (0.059 mol) of 2,2'-methylenebis(4,6-di-tert-butylphenol) and 0.57 mL (5.9 mmol) of 1-methyl-2-pyrrolidinone in 275 mL of toluene at ambient temperature is added dropwise 5.16 mL (0.059 mol) of phosphorus trichloride. After the addition is complete, the reaction mixture is refluxed for eight hours. After cooling the mixture to ambient temperature, the toluene is removed in vacuo and the reaction mass is recrystallized twice from 250 mL of 98% acetonitrile and 2% toluene (% by volume) in acetonitrile. The recrystallization solvent is removed by decantation and the residue is dried under vacuum to give 21.4 g (79% yield) of the title compound as an off-white solid melting at 227°-230° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:5]4[CH:6]=[C:7]5[C:11](=[C:3]([CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:4]=4)[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]5)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CNS(C)(=O)=O)c2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Methanesulfonyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 12 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-(methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 483.2, found 484.3(M+1)+. Retention time of 1.84 minutes.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[C:29](=[O:32])([O-])[OH:30].[Na+].[OH-].[Na+].[O:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(O)C>[CH:1]1([CH:7]([NH:11][C:10]2[CH:9]=[CH:7][C:39]([C:40]([NH:12][CH2:14][CH2:19][C:29]([OH:30])=[O:32])=[O:36])=[CH:38][CH:37]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution (10 mL) of cyclohexyl{3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized above in tetrahydrofuran was added thionyl chloride (0.24 mL) at room temperature, and the mixture was stirred for 30 min. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 mL), and sodium iodide (0.63 g), sodium carbonate (0.45 g) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.75 g) synthesized in Example 1, (2) were added. The mixture was stirred at 80° C. overnight and allowed to cool. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound in an ethyl ester form (876 mg). This was dissolved in ethanol (4 mL), 1N aqueous sodium hydroxide solution (4 mL) was added at room temperature, and the mixture was stirred for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (4 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.78 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(=O)C)=[C:5]([C:11]#[C:12][Si](C)(C)C)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.C([OH:25])C.[OH-].[Na+]>C(OCC)(=O)C.O>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:11](=[O:25])[CH3:12]
Reactant: CC(=O)Nc1c(C#C[Si](C)(C)C)c(-c2ccccc2)nn1C
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1c(-c2ccccc2)nn(C)c1N
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of N-(1-methyl-3-phenyl-4-((trimethylsilyl)ethynyl)-1H-pyrazol-5-yl)acetamide (2.3 g, 7.4 mmol), ethanol (20 mL) and 25% aq. NaOH solution (20 mL) was heated with stirring at 90° C. for 6 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. The residue was purified using chromatography (silica gel, gradient 0 to 40% ethyl acetate/CH2Cl2), followed by trituration in diethyl ether to provide the title compound as a white solid (724 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(F)cc3)c3c(F)cc(F)cc23)CC1

Procedure:
(7.6 mg, 46.4%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmoles) and 4-fluorophenylsulfonyl chloride (11.7 mg, 0.06 mmol) with 1M NaN(TMS)2 (60 μL, 0.06 mmoles) in THF (0.5 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)=[O:31])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2c(Br)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 124 μmol, from step 3, example 146), CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (17 mg, 124 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-bromo-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 493 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[C:3]=1I.[C:15](=O)([O-])[O-:16].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]=1[O:16][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1c(C(=O)O)nc(Cl)c(F)c1N
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a dry 1 liter (L) flask was added methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (50 g, 151 mmol) and cesium carbonate (Cs2CO3; 99 g, 303 mmol). CH3OH (378 mL) was added, and the solution was sparged with nitrogen for 10 min. 1,10-Phenanthroline (6.00 g, 30.3 mmol) and copper(I) iodide (CuI; 2.88 g, 15.13 mmol) were added, and the flask was fitted with a reflux condenser and heated to 65° C. under nitrogen. After 12 h, CuI (2.88 g, 15.13 mmol) was again added to the reaction mixture, and heating was continued until consumption of the iodopicolinate was observed. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated in vacuo. To the crude residue was added EtOAc (100 mL) and H2O (100 mL). The layers were separated, and the aqueous phase was acidified to pH=2 with concentrated (conc) HCl and subsequently extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with satd aq NaCl, dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-amino-6-chloro-5-fluoro-3-methoxypicolinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9](=N)[C:10](Cl)(Cl)Cl)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]([C@H:21]1[CH2:25][C@@H](O)C[N:22]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:20].CO>C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[La+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:17][O:18][C:19]([C@H:21]1[CH2:25][C@@H:9]([O:8][CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][N:22]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[O:20]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [La+3]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](OCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
Add lanthanum triflate (3.6 g, 6.16 mmol) to a solution of 2,2,2-trichloro-acetimidic acid 4-methoxybenzyl ester (52.2 g, 185 mmol) and (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (30.2 g, 123 mmol) in toluene (200 mL). Stir 2.5 h, add methanol and concentrate. Dissolve in 25:75 dichloromethane:hexanes, filter away the insolubles and purify filtrate (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (37.85 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)=[O:9]
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-benzoic acid (50.0 mg, 0.177 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (114.4 mg, 151 μL, 0.89 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (80.8 mg, 0.21 mmol, 1.2 equiv; [CAS RN 148893-10-1]). After stirring of the reaction mixture at 50° C. for 1 h, 1,2,3,4-tetrahydro-quinoline (28.3 mg, 27 μL, 0.21 mmol, 1.2 equiv; [CAS RN 635-46-1]) was added and stirring at 50° C. continued over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12.9 mg (18%) of the title compound. MS (ISP): 398.2 [M+H]+.
Reaction SMILES: [Br-:1].[Br-:2].[Br-:3].[Al+3].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1.C1(C)C(C)=CC=CC=1.[Br:21]Br>>[Br:1][C:8]1[C:9]([CH3:12])=[C:10]([Br:2])[C:11]([Br:3])=[C:6]([CH3:5])[C:7]=1[Br:21]
Reactant: BrBr
Reactant: [Br-]
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Solvent: Cc1ccccc1C
Product: Cc1c(Br)c(Br)c(C)c(Br)c1Br
Temperature: 5 °C
Yield: 98.3 %

Procedure:
In a glass resin flask, a mixture of 1000 parts bromine and 3 parts of aluminum tribromide was cooled at 5° C and 83 parts of p-xylene were added dropwise with rapid stirring and continued cooling. After adding about 3/4 of the xylene, the reaction mixture became viscous forming large chunks of product. The mixture was diluted with 454 parts of bromine and the temperature was brought to 30° C. The heating and stirring gradually broke down the chunks of product to a fine powder. The mixture was then cooled to 15° C and the remaining xylene was added. Most of the excess bromine was removed by distillation. The solid was removed from the reaction flask and leached with cold methanol to remove excess bromine. The product was then dissolved in hot benzene and filtered. The solvent was then driven off and 323 parts (98.3% yield) of tetrabromo-p-xylene was obtained as crystals having the melting point of 253°-254° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)C=C.CN1[CH2:20][CH2:19][O:18]CC1.S(S([O-])=O)([O-])=[O:22].[O-][Si]([O-])=O.[Mg+2]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:13][C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:19]([OH:18])[CH2:20][OH:22])=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: C=CCc1ccc(C(C)(C)O)cc1
Reactant: CN1CCOCC1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)c1ccc(CC(O)CO)cc1
Reaction time: 24 h

Procedure:
To a biphasic mixture of 2-(4-allylphenyl)propan-2-ol (5.53 g, 31.4 mmol) and N-Methyl morpholine NV oxide (3.86 g, 32.9 mmol) in acetone (11 mL) and water (22 mL) was added osmium tetroxide (3.14 mL, 0.157 mmol) with vigorous stirring. After 24 hours, dithionite (0.15 g), Florisil (1.5 g), and water (8 mL) were added and allowed to stir for an additional 15 minutes before filtering through a pad of Celite. The filter was rinsed with acetone (2×5 mL, then 2×10 mL), and filtrate was concentrated by rotary evaporation to remove the acetone. The remaining liquid was diluted with 9:1 chloroformisopropanol (20 mL) and aqueous hydrogen chloride (1 M, 20 mL), the layers were separated, and the acidic (pH=1) aqueous layer was extracted with 9:1 chloroformisopropanol (2×20 mL). The combined organic layers were washed with 3:1 water:brine (12 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The aqueous layers were combined and saturated with solid sodium chloride (50 cc) by stirring for 90 minutes, and then extracted with 9:1 chloroformisopropanol (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated, and the crude material was purified by silica gel chromatography (5-20% methanol/dichloromethane) to afford 3-[4-(1-hydroxy-1-methylethy)phenyl]propane-1,2-diol as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1>>[F:25][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][C:15]([OH:26])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(O)c(F)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1ccc(CCC(=O)O)cc1F
Yield: 72.5 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.030 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.038 g, 73%).