Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([I+:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:46][C:45]([CH3:48])([CH3:47])[C:44]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:49].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([I+:26][C:23]2[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
Into a mixture solution of 6.5 g (0.010 mole) of bis(4-tert-butylphenyl)iodonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-13, 2.2 g (0.022 mole) of triethylamine, 0.2 g (0.002 mole) of 4-dimethylaminopyridine, and 25 g of methylene chloride was added 2.4 g (0.020 mole) of pivaloyl chloride, and they were stirred at room temperature for 8 hours. Thereafter, the reaction was terminated by adding 22 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended bis(4-tert-butylphenyl)iodonium 2-(2,2-Dimethylpropionyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.8 g of white crystals (yield 23%)). The structure of the intended product is shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>CCOCC.C([O-])(=O)C.[Na+]>[C:10]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])(=[O:11])[CH2:9][C:8]([CH3:7])=[O:12]
Reactant: CC(C)=CCO
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)OCC=C(C)C
Yield: 75.4 %

Procedure:
A mixture of 3-methyl-2-buten-1-ol (21.2 g, 0.25 mole) and anhydrous sodium acetate (0.1 g) was cooled to 0°. Diketene (36 ml, 0.3 mole) was added dropwise over a period of 1.5 to 2 hours. The reaction mixture was then heated to 75°-80°, and this temperature was maintained for one hour. The mixture was diluted with ether. The ethereal solution was washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over magnesium sulfate. The ether was evaporated, leaving a residue which was distilled under vacuum, affording 3-methyl-2-butenyl acetoacetate (32.1 g, 76% yield); bp 114°-117°/18-19 mm.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(=O)c(O)c(CO)o1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Yield: 80 %

Procedure:
Sodium hydroxide (4.84 g, 121 mmol, 1.1 eq.) dissolved in 10 ml distilled water was added to 100 ml methanol containing 2-hydroxymethyl-3-hydroxy-6-methyl-pyran-4(1H)-one (17.2 g, 110 mmol, 1 eq.) and heated to reflux. Benzyl bromide (20.7 g, 121 mmol, 1 eq.) was added dropwise over 30minutes and then refluxed overnight The reaction mixture was concentrated in vacuo, the residue taken up into 300 ml dichioromethane and the inorganic salts filtered off. The dichloromethane layer was washed with 2×100 ml 5% w/v sodium hydroxide solution, 100 ml water, dried (Na2SO4), and concentrated in vacuo to yield the crude product as a yellow crystalline solid. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the title product in 80% yield (21.6 g) as a white crystalline solid. m p. 115-116° C. [lit 114-116° C. Tilbrook (1995)].
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[S:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1>C1(C)C=CC=CC=1.ClCCl>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:34]([C:32]1[N:31]=[CH:30][S:29][CH:33]=1)[OH:35]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: O=Cc1cscn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cscn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 89.7 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (200 mg, 0.7 mmol) in anhydrous toluene (8 mL), TMEDA (110 uL, 0.7 mmol) was added followed by nBuLi (0.47 mL, 0.75 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and a solution of thiazole-4-carbaldehyde (0.32 g, 2.8 mmol) in dichloromethane (1 mL) was added. The mixture was stirred for 16 hrs during which the temperature reached room temperature. The reaction was quenched with water, the resulting mixture was basified by the addition of NH4OH and extracted with EtOAc. The combined organic layers were concentrated and subjected to mass triggered preparative HPLC to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (Compound 14-1) (200 mg). MH+=318.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N:32]([C@@H:35]([CH:40]([CH3:42])[CH3:41])[C:36]([O:38][CH3:39])=[O:37])=[C:33]=[O:34].O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:26][CH2:27][C@H:28]([O:31][C:33](=[O:34])[NH:32][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:30]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(NC(=O)O[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1)C(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5-cyclohex-1-enyl-3-{(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino}-thiophene-2-carboxylic acid (20 mg, 0.045 mmol) and methyl (S)-(−)-2-isocyanato-3-methylbutyrate (10 μl, 0.07 mmol) in toluene (1 mL) was stirred at 70° C. for 2 h. It was cooled and water (1 mL) was added. The mixture was stirred at room temperature for one h. It was extracted with EtOAc (50 mL), washed with brine, dried (MgSO4) and evaporated. Pure 5-cyclohex-1-enyl-3-[{trans-4-(1-methoxycarbonyl-2-methyl-propylcarbamoyloxy)-cyclohexyl}-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained by chromatography over silica gel (hexane-EtOAc mixtures, pure EtOAc and 5% acetone in DCM as eluent) (12.4 mg, 45%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.CC1C=CN=C(NC2C=CC=C(C3OC=NC=3)N=2)C=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I:50]C(I)C>C1COCC1>[I:50][C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Reactant: CC(I)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)n2)c1
Yield: 41 %

Procedure:
The 2-iodooxazole derivative was prepared as for [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine above from (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine with LiHMDS (1M solution in THF) and diiodoethane in anhydrous THF to give the title compound as a yellow solid (41%) after purification by column chromatography on SiO2 eluting with 40% EtOAc in cyclohexane. 1H NMR (300 MHz, DMSO-d6) δ=9.81 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.84-7.51 (m, 4H), 7.23 (d, J=7.2 Hz, 1H), 6.77 (d, J=4.6 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:23][C:22]4[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:21]=4[F:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Cc1ccc(F)c(N)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Cc1ccc(F)c(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-fluoro-5-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.11 (dd, 1H, J=1.8 and 8.1 Hz), 7.94 (d, 1H, J=2.7 Hz), 7.08-6.84 (m, 4H), 6.74-6.67 (m, 1H), 6.64-6.59 (m, 1H), 4.27 (s, 4H), 2.28 (s, 3H); 19F NMR (282 MHz, CDCl3): −38659, −47267; LCMS: purity: 100%; MS (m/e): 371 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]([C:21]2[C:22]([OH:30])=[N:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl.[NH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][NH:32][C:27]([C:24]1[N:23]=[C:22]([OH:30])[C:21]([C:19](=[O:20])[NH:18][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:26][N:25]=1)=[O:28]
Reactant: COC(=O)CN
Reactant: COc1ccc(C(NC(=O)c2cnc(C(=O)O)nc2O)c2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ncc(C(=O)NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of compound 2-17-e (2.5 g, 6.1 mmol), methyl 2-aminoacetate hydrochloride (0.92 g, 7.3 mmol), TBTU (2.4 g, 7.3 mmol), DIPEA (1.6 g, 12.2 mmol) in DMSO (15 mL) and stirred at the ambient temperature overnight. Ice-water was then added to the reaction mixture and filtered. The cake was purified by column chromatography with DCM:MeOH=100:1˜50:1 to obtain the product, 2-17-f, (630 mg, 22%). LC-MS: (M+H)+ 481.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (75 mg, 0.21 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (42 mg, 1.05 mmol, 4.94 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aqueous hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 80% in 8 min, up to 100% in 1.5 min); Detector, uv 220&254 nm. This resulted in 20 mg (27%) of 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH2:27]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:34]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)N(CCCCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCNCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccccc1)N(CCCCCC(=O)N(CCCC(=O)O)Cc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-6-(1-phenylethylamino)caproic acid and ethyl 4-benzylaminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-6-(1-phenylethylamino)hexanoyl]-4-benzylaminobutyric acid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)S(C)(=O)=O)OCC
Yield: 63.1 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (45 mg, 0.092 mmol) in CH2Cl2 (0.5 mL) was stirred with methanesulfonyl chloride (21 μL, 0.28 mmol) and pyridine (45 μL, 0.55 mmol) at ambient temperature overnight. The reaction was quenched by addition of 2 drops of water. The reaction mixture was concentrated and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 36 mg of the product (63%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H), 1.29 (t, 6H, J=7 Hz), 1.85 (s, 3H), 2.00-2.13 (m, 2H), 2.19 (s, 3H), 2.85 (s, 3H), 3.32-3.43 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.69 (s, 2H), 3.79 (s, 3H), 4.05 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H), 5.45 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CD3Cl) δ 27.5 ppm; MS (m/z) 642.2 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][N:11]1[C:3]2[C:4](=[N:5][C:6]([CH3:8])=[CH:7][CH:2]=2)[CH:9]=[N:10]1
Reactant: COCCN
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Product: COCCNn1ncc2nc(C)ccc21

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) (1 g, 0.06 mole) was heated at reflux under nitrogen in methoxyethylamine for 1 week. Volatile material was removed under vacuum and the residue treated with water (15 ml) and a little methanol. A small amount of insoluble material was filtered off and the filtrate reevaporated to dryness. Chromatography on basic alumina eluting with ethyl acetate with methanol added to a maximum of 15% gave white gum. This was further purified by passing through Dowex 50W column, previously treated with dilute HCl, eluting initially with methanol, then water and finally 5% 0.880 ammonia in water. The fractions containing UV active material were freeze dried giving the title compound as a white solid (0.38 g,31%) m.p. 167°-170° (Found: C, 57.18; H, 6.84; N, 27.06 C10H14N4O.O.2H2O requires C,57.23; H, 6.90; N, 26.70%), δ(DMSOd-6) 2.4 (3H,s), 3.2-3.7 (4H,m), 6.25 (1H,s), 6.35 (1H,br.s), 7.9 (1H,s).
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:15])[N:7]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2[nH]c3cccc(F)c3c12
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cccc2c1c1c(F)cccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4,5-difluoro-9H-carbazole (0.270 g, 1.3 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.105 g, 1.6 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.220 mL, 2.7 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 4 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.315 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.45 (tt, 2H, J=8.1, 2.4 Hz), 7.25 (d, 2H, J=8.1 Hz), 6.99 (dt, 2H, J=9.9, 4.2 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.38 (dd, 1H, J=15.9, 5.1 Hz), 3.37 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[SH2:29].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O>C(Cl)Cl>[SH:29][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 70.4 %

Procedure:
A solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (1 g) and tetrabutylammonium hydrogen sulfide (0.7 g) in methylene chloride (10 ml) is stirred at -10° C., for 20 minutes, neutralized with a drop of AcOH, evaporated under vacuum and the residue recrystallized from Et2O to give 0.7 g of 2-mercaptomethyl-3,5-dicarboetoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[N:8]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:41])[F:42])=[CH:40][CH:39]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Temperature: 0 °C

Procedure:
4,6-dichloro-3H-imidazo[4,5-c]pyridine (500 mg, 2.6 mmol), PPh3 (762 mg, 2.91 mmol) and THF (20 mL) were combined and stirred under a nitrogen atmosphere. A solution of 4-trifluoromethyl benzyl alcohol (513 mg, 2.91 mmol) in THF (5 mL) was added at rt. The reaction mixture was cooled to 0° C., and diisopropyl azodicarboxylate (587 mg, 2.91 mmol) was added dropwise. The reaction was warmed to rt and stirred overnight under N2. The reaction was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was dissolved in EtOAc (20 ml), p-toluenesulfonic acid (500 mg, 2.91 mmol) was added at rt, and the mixture was stirred for 3 h. The precipitate which formed was collected by filtration and rinsed with EtOAc. The collected precipitate was slurried in EtOAc (50 mL) and was stirred vigorously with aqueous sat'd NaHCO3 (5 mL) for 30 min. The organic layer was separated, and the aqueous layer was extracted several times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatograhy with 20% to 100% EtOAc/hexanes to obtain the desired isomer, 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine. 1H NMR (400 MHz, CDCl3): δ8.85 (s, 1H); 7.96 (s, 1H); 7.71 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.89 (s, 2H). MS APCI calc'd. for C14H8Cl2F3N3 [M+H]+ 346. found 346.