Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Next, 0.85 g (1.57 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(4-nitrophenyl)phosphono]butanoate and 1.02 g (9.42 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.63 g (4.71 mmol) of aluminum trichloride. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was separated, and methanol was added to adjust the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, 30 mL of the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min and the fractions containing the compound eluted at 48% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[methyl(4-nitrophenyl)phosphono]butanoic acid (0.35 g, yield 70%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O)=[O:2].Cl>[Fe].C(O)C>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH:1]=[O:2])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(C=O)c(N)c1
Reaction time: 0.25 h

Procedure:
To a solution of 25 mL of ethanol/glacial acetic acid/water (2:2:1) were added 0.6 g (2.9 mmol) of methyl 4-formyl-3-nitrobenzoate, 1.2 g (21.4 mmol) of iron powder and 0.01 mL of concentrated hydrochloric acid and the mixture was refluxed with stirring for 15 minutes. Then the iron was separated off, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried, and evaporated down. Yield: 0.3 g (58% of theory); Rf value: 0.74 (silica gel, methylene chloride/methanol=9.5:0.5).
Reaction SMILES: Cl[C:2]1[CH:31]=[N:30][C:5]2[S:6](=[O:29])(=[O:28])[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]([N:9]1[CH2:8][CH2:7][S:6](=[O:29])(=[O:28])[C:5]3[N:30]=[CH:31][C:2]([N:66]4[CH2:71][CH2:70][O:69][CH2:68][CH2:67]4)=[CH:3][C:4]1=3)=[C:11]([CH3:27])[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:13]2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ncc(Cl)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ncc(N3CCOCC3)cc21
Temperature: 25 °C

Procedure:
Prepared according to procedure N by heating a solution of 7-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide (34 mg, 0.075 mmol), Pd2dba3 (6.8 mg, 7.5 μmol), XPhos (7.13 mg, 0.015 mmol), morpholine (6.51 μL, 0.075 mmol) and sodium tert-butoxide (14.4 mg, 0.149 mmol) in toluene (2.0 mL) in the microwave for 2 h at 110° C. After this time the reaction was cooled to rt and partitioned between EtOAc (60 mL) and NaHCO3 (20 mL, saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-7-(4-morpholinyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]-thiazine 4,4-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dt, J=4.8, 1.5 Hz), 8.05-8.12 (1H, m), 7.94 (2H, dt, J=4.6, 0.9 Hz), 7.87 (1H, d, J=2.3 Hz), 7.70 (1H, td, J=8.2, 5.4 Hz), 7.44 (1H, q, J=4.8 Hz), 7.23-7.30 (1H, m), 5.62 (1H, d, J=2.3 Hz), 4.17-4.32 (2H, m), 3.64-3.76 (5H, m), 3.49-3.60 (1H, m), 2.87-3.04 (4H, m), 2.46 (3H, s). Mass Spectrum (ESI) m/e=506.0 (M+1).
Reaction SMILES: ClC1C(OC)=C(OC)C=CC=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36]Cl)[C:24]2[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].[Na+].[I-].C[C:45]([CH3:47])=O>>[CH3:19][CH:17]([CH3:18])[CH2:16][CH2:15][N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:34][CH2:35][CH2:36][N:22]2[CH2:47][CH2:45][N:14]([CH3:12])[CH2:20][CH2:21]2)[C:24]2[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=2[N:22]=1)[CH:12]=[O:13]
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2OCCCCl)c(Cl)c1OC
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCN(C=O)Cc1nc2ccccc2n1Cc1ccccc1OCCCN1CCN(C)CC1
Temperature: 25 °C

Procedure:
A solution of 395 mg (0.66 mmole) of (2-chloro-3,4-dimethoxyphenyl)-N-[(1-{[2-(3-chloropropoxy)phenyl]-methyl}benzimidazol-2-yl)methyl]-N-(3-methylbutyl) carboxamide in 6 mL of acetone is treated with 99 mg (3.30 mmole) of NaI at reflux for 16 hrs, at which time another 3.30 mmole of NaI is added and heated for an additional 24 hrs. The solution is evaporated under reduced pressure, the residue is diluted with 30 mL of ethyl acetate, washed with 2×10 mL water and 1×10 mL brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The residue is dissolved in anhydrous 1-methyl-2-pyrrolidinone at 100 mg/ mL and 1 mL of the solution is treated with an excess of N-methyl piperazine at 50° C. for 16 hr. The resulting solution is cooled to room temperature, washed with 3×1 mL water and 1×1 mL brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The residue is prep-plate chromatographed (5% MeOH/CH2Cl2/0.5% NH4OH) to afford 65 mg (70%) of 2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)-N-{[1-({2-[3-(4-methylpiperazinyl)propoxy]phenyl}methyl)benzimidazol-2-yl]methyl}carboxamide. Mass Spec M+ 663.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[N:20][CH:21]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>CCO>[ClH:34].[ClH:34].[OH:27][NH:26][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]1[CH:18]=[N:17][C:16]([NH:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)=[CH:21][N:20]=1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCc3ccccc3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(CCc3ccccc3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To the solution of (2E)-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (3.2 g, 7.1 mmol) in EtOH (16 ml) was added 2M ethanolic hydrogen chloride (17.5 mL) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added IPE and isolated precipitate was collected by filtration to give (2E)-N-hydroxy-3-(5-{[(3R)-1-(2-phenylethyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylamide dihydrochloride (2.3 g, 74%) as an amorphous powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]#[CH:20].Cl>C(C(C)=O)C>[CH2:20]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[C:19]#[CH:18]
Reactant: C#CCBr
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCSc1ccccc1C(=O)O
Reaction time: 3 h

Procedure:
To thiosalicylic acid (77 g) slurried in methyl ethyl ketone (500 ml) was added 1 equivalent of K2CO3 followed by 3-bromopropyne (1 equivalent). The reaction mixture was stirred for 3 hours and then poured into 1N HCl and the solids filtered and then vacuum dried to afford the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#Cc1ccc(N)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1
Yield: 51.9 %

Procedure:
Using general procedure A, 4-aminobenzonitrile (1.19 g, 10.1 mmol) and 1-Boc-4-piperidone (2.05 g, 10.3 mmol) gave 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.58 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:18])[CH:12]=[CH:13][C:14]=1[F:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:28])([CH3:27])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[OH:18])[CH:12]=[CH:13][C:14]=1[F:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1C(=O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C(O)C(C)(C)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a mixture of 2-[3-(tert-butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanone (0.59 g) in tetrahydrofuran (7.5 mL)-water (0.75 mL) was added sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2-[3-(tert -butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methyl-1-propanol (0.54 g). This material was dissolved in ethanol (8 mL)-tetrahydrofuran (3 mL). To the solution were added 2 mol/L hydrochloric acid (0.2 mL) and 10% palladium-carbon powder (0.27 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. To the reaction mixture was added sodium hydrogen carbonate, and the mixture was stirred for 10 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/1) to give 2-[3-(tert -butoxycarbonylamino)-4-fluorophenyl]-1-(2-methoxyphenyl)-2-methylpropane (0.15 g). To this material was added hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.OO.[OH2:11]>CC(O[Na])=O>[C:1]1([OH:11])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: Nc1ccc(N)cc1
Agent: CC(=O)O[Na]
Agent: OO
Product: Oc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the materials listed above were wetted in DI water and soaked in the precursor solutions. A Coprinus cinereus peroxidase ("CiP") with an activity of 180,000 POXU/ml was added to each beaker at a concentration of 0.05 POXU/ml. Either 200 or 500 μM hydrogen peroxide was added to each LOM beaker. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30° C., the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature and CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 38-41.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br>C(Cl)Cl>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][OH:12])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[OH:1])=[O:15]
Reactant: COc1cc(O)c(C(C)=O)cc1CCO
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(O)c(C(=O)CBr)cc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 mL of methylene chloride was dissolved 10.0 g of 1-[2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone, and 2.94 mL of bromine was added dropwise to the solution, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.4 g of 2-bromo-1-[2-hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone as a yellow oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:54]1([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:62]3[CH2:63][CH2:64][CH:59]([N:54]4[CH2:58][CH2:57][CH2:56][CH2:55]4)[CH2:60][CH2:61]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reaction time: 16 h
Yield: 90.1 %

Procedure:
7.20 g (17.5 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) were dissolved in 290 ml of DMF and treated with 6.846 g (17.5 mmol) of HATU. 7.30 ml=5.30 g (52.4 mmol) of Et3N were added and after 30 min, a solution of 2.72 g (17.5 mmol) of 4-pyrrolidin-1-yl-piperidine in 70 ml of DMF was added. After 16 hours, the reaction mixture was poured into crashed ice and extracted three times with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 8.65 g (90%) of the title compound as light brown foam. MS: 549.3 (MH+).
Reaction SMILES: C(O)CCCCCCCO.FC1C=C(C=CC=1C(F)(F)F)CBr.[F:24][C:25]1[CH:26]=[C:27]([CH:39]=[CH:40][C:41]=1[C:42]([F:45])([F:44])[F:43])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38].FC1C=C(C=CC=1C(F)(F)F)COCCCCCCCC(O)=O.Cl.Cl.[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH2:86])[CH2:82][N:83]([CH3:85])[CH3:84])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:71]([O:78][C:79](=[O:87])[CH2:80][C@@H:81]([NH:86][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]1[CH:39]=[CH:40][C:41]([C:42]([F:43])([F:44])[F:45])=[C:25]([F:24])[CH:26]=1)[CH2:82][N:83]([CH3:84])[CH3:85])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: OCCCCCCCCOCc1ccc(C(F)(F)F)c(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1cc(CBr)ccc1C(F)(F)F
Agent: O=C(O)CCCCCCCOCc1ccc(C(F)(F)F)c(F)c1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound, m/e=463.5 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 3-fluoro-4-trifluoromethyl-benzyl bromide, leading to 8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(3-fluoro-4-trifluoromethyl-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)[C:8]=1[CH3:22]>C1COCC1.CO>[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:23])=[O:4])=[C:8]2[CH3:22])=[CH:18]1
Reactant: COC(=O)Cc1c(C)n(Cc2ccoc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccoc1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.25 mL) is added to a stirring solution of (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (7.5 mg, 0.026 mmol) in 1:1 THF/MeOH (1 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 3-4, and extracted with EtOAc. The organic layer is washed with water then brine, dried (MgSO4), then evaporated to furnish (1-furan-3-ylmethyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid; MH+=271.
Reaction SMILES: [C:1]([O:4][CH:5](P(CC)(CC)=O)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[Cl-].[Li+].CN(C)C(=N)N(C)C.[CH3:26][O:27][CH2:28][N:29]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:40])=[CH:33][C:34]([CH:38]=O)=[CH:35]2)=[N:30]1>O1CCCC1>[C:1]([O:4][C:5](=[CH:38][C:34]1[CH:33]=[C:32]([CH3:40])[C:31]2[C:36](=[CH:37][N:29]([CH2:28][O:27][CH3:26])[N:30]=2)[CH:35]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COCn1cc2cc(C=O)cc(C)c2n1
Reactant: CCP(=O)(CC)C(OC(C)=O)C(=O)OC
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCn1cc2cc(C=C(OC(C)=O)C(=O)OC)cc(C)c2n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-acetoxy-2-(diethylphosphoryl)acetate (4.89 g, 18.2 mmol) in tetrahydrofuran (25 mL) was added lithium chloride (0.74 g, 17.5 mmol). The reaction was stirred until dissolution was complete. The reaction was cooled to −78° C., and treated with tetramethylguanidine (2.20 mL, 17.5 mmol) to give a white suspension which was stirred for 10 min. To this was added 2-(methoxymethyl)-7-methyl-2H-indazole-5-carbaldehyde (3.10 g, 15.2 mmol) in one portion. After 10 min, the ice bath was concentrated and the reaction stirred overnight. The reaction was poured onto water/diethyl ether, and the layers separated. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography gave recovered 2-(methoxymethyl)-7-methyl-2H-indazole-5-carbaldehyde (0.57 g, 18%) and the title compound (2.86 g, 59%) as a colorless oil. NMR shows a 3:2 ratio of Z and E isomers which were not separated. Major (Z isomer): 1H-NMR (CDCl3, 500 MHz) δ 2.25 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.71 (s, 3H), 5.69 (s, 2H), 6.88 (s, 1H), 7.09 (s, 1H), 7.72 (s, 1H), 8.10 (s, 1H). Mass spec.: 319.18 (MH)+. Minor (E isomer): 1H-NMR (CDCl3, 500 MHz) δ 2.35 (s, 3H), 2.62 (s, 3H), 3.40 (s, 3H), 3.85 (s, 3H), 5.69 (s, 2H), 7.32 (s, 1H), 7.38 (s, 1H), 7.78 (s, 1H), 8.14 (s, 1H). Mass spec.: 319.18 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.COCC(O)C.C(N(CC)C(C)C)(C)C.Cl>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)=[N:37]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: Cl
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(OC4CCNCC4)c3)nn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.32 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), 1-Methoxy-2-propanol (0.3 mL, 3 mmol), and N,N-Diisopropylethylamine (2 mL, 10 mmol) was heated and let stir overnight at 80° C. Concentrated added Hydrogen Chloride (2 mL, 60 mmol) and stir at room temperature for half and hour. The reaction was concentrated, dissolved in 2 mL DMSO, filtered and placed onto the Gilson. The pure fractions were frozen and lypholyzed over night to give [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(piperidin-4-yloxy)-phenyl]-amine
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[C:11]([C:36]#[N:37])=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=3)[S:13][C:14]=2[C:15]2[N:19]=[CH:18][N:17](C3CCCCO3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[C:11]([C:36]#[N:37])=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=3)[S:13][C:14]=2[C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(S(=O)c3ccc(Cl)cc3)c2C#N)ccn1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(S(=O)c3ccc(Cl)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
N-(4-(4-(4-chlorophenylsulfinyl)-3-cyano-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide (0.0315 g, 0.0570 mmol) was dissolved in TFA (5.00 mL, 64.9 mmol). The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated. 10 ml DCM was added to redissolve the material followed by the addition of triethylamine (1 mL). The solvent was evaporated off, and the mixture was purified by silica gel column. The eluent was 0-6% methanol in hexane to yield a solid product (0.0112 g, yield 41.9%) LCMS: (AA) ES+ 469, 471. 1H NMR (300 MHz, MeOD) δ: 8.65 (s, 1H), 8.51 (s, 1H), 8.42 (d, 1H), 8.06 (d, 2H), 7.58 (d, 2H), 7.44 (dd, 1H), 2.25 (s, 3H).