Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A mixture of 0.397 g (1 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2), 0.24 g (1.2 mmol) of tert-butyl 4-amino-1-piperidinecarboxylate, and 0.194 g (1.5 mmol) of DIPEA in 25 mL of THF was stirred at room temperature overnight. Dilution with water and extraction with CH2Cl2, followed by chromatography on silica eluting with CH2Cl2/EtOAc (4:1) gave 0.51 g (91% yield) of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate: mp (hexanes/CH2Cl2) 142-145° C.; 1H NMR (CDCl3) (rotamer mixture; ratio ca. 3:2) δ 7.96 and 7.95 (2d, J=8.3 and 7.9 Hz, 1H), 7.54 and 7.52 (2t, JHF=53.6 Hz, 1H), 7.34 (br t, J=8.1 Hz, 1H), 6.81 (t, J=6.9 Hz, 1H), 5.22 and 5.17 (2d, J=7.4 and 7.6 Hz, exchangeable with D2O, 1H), 4.10 (m, 3H), 4.05 (s, 3H), 3.87 (m, 4H), 3.78 (m, 4H), 2.93 (t, J=12.1 Hz, 2H) 2.06 (m, 2H), 1.48 (s, 9H), 1.43 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.6; H, 6.2; N, 20.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31]C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:33][CH:34]=1)=[O:11]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 72 °C

Procedure:
To a stirred solution of methyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate (1.38 g, 3.00 mmol) in a mixture of solvents THF/MeOH (20 ml/20 ml) was added 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a 72° C. bath for 5 hours, cooled to room temperature and poured into 200 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 1.28 g, 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[NH:5][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(3-chloroanilino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(3-chloroanilino)-4-phenethylbenzoic acid 21 mg of white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[CH:17][C:9]2[O:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][C:12]1([CH3:16])[CH2:11][O:10][C:9]2[CH:17]=[CH:18][C:6]([CH2:4][OH:3])=[CH:7][C:8]=2[O:14][CH2:13]1
Reactant: CCOC(=O)c1ccc2c(c1)OCC(C)(C)CO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(CO)cc2OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
3,3-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carboxylic acid ethyl ester (30) (9.00 g) is dissolved in THF (150 ml) and a 1.5 M solution of diisobutylaluminium hydride in toluene (120 ml) is slowly added. The resulting reaction mixture is stirred 1 h at RT, then cooled to −30° C. and H2O (120 ml) is cautiously added. After letting the temperature rise to RT a 20% aq. HCl solution (100 ml) is added. The ether layer is collected, washed with H2O and dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, hexane/AcOEt 4:1) yields 7.25 g of (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31), MS (ESI) 208.1 (M•)+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH2:15].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][CH2:14][NH:15][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCNCC(O)C(=O)O)cc1OC
Temperature: 110 °C
Yield: 57.1 %

Procedure:
A mixture of 20 g (0.16 mole) of β-chlorolactic acid and 86 g (0.48 mole) of 3,4-dimethoxyphenethylamine was heated at 110° C. for 15 hours. The resulting product was dissolved in about 200 ml of water and the pH was adjusted to about 8 with Na2CO3. The aqueous solution was extracted with 2×500 ml of chloroform and neutralized to pH 7 with diluted HCl. The solution was evaporated to dryness and the residue was recrystallized in EtOH to give 24.6 g (61.6%) of crystals: m.p. 187.5°-188.5° C. The NMR, IR and mass spectra were consistent with the assigned structure, and the elemental analysis was consistent with the empirical formula, C13H19O5N.
Reaction SMILES: [CH2:1]([C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[C:10](=[O:29])[CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[C:10](=[O:29])[CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccccc1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Dissolve 3-[(2-benzylphenacyl)amino]-2-carbethoxy-4,6-dichloroindole (100 mg, 0.214 mmol) in tetrahydrofuran (7 mL) and water (7 mL). Add lithium hydroxide monohydrate (25.2 mg, 6 mmol) and stir overnight. Stir at 40° C. for 2 hours, dilute with water (10 mL) and ethyl acetate (25mL). Acidify with 1N hydrochloric acid while stirring. Separate the organicphase, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ether/hexane) to give the title compound (89 mg, 95%); mp 234°-235° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].FC(F)(F)C(O)=O>>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)C(=O)N(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)C(=O)N(C)C)c3)cc12

Procedure:
To the crude 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-N,N-dimethyl-acetamide obtained in last step was added trifluoroacetic acid (2 mL) and the resulting mixture was sonicated until the residue was completely dissolved. The trifluoroacetic acid was evaporated and the residue treated with ethylene diamine (0.2 mL). The resulting mixture was purified via mass-triggered reverse-phase HPLC to yield 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-N,N-dimethyl-acetamide as a white solid (25 mg, 33% over two steps). MS: m/z 403 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.89 (d, 6H), 3.87 (s, 3H), 5.48 (d, 1H), 5.57 (d, 1H), 7.10 (t, 1H), 7.24 (d, 1H), 7.38 (d, 1H), 7.47 (dt, 1H), 7.48 (t, 1H), 7.67 (dd, 1H), 7.70 (d, 1H), 7.75 (s, 1H), 8.32 (d, 1H), 8.84 (d, 1H), 13.84 (s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]([CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:25])[CH:12]([CH3:24])[N:13]1C(=O)C2C(=CC=CC=2)C1=O.CN.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C)C=O.O>[ClH:1].[ClH:1].[NH2:13][CH:12]([CH3:24])[C:11]([N:10]([C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:25]
Reactant: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)C(C)N1C(=O)c2ccccc2C1=O
Agent: CN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)C(C)N
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a solution of 45.0 g of rac-2,3-dihydro-N-(2,6-dimethylphenyl)-alpha-methyl-1,3-dioxo-N-[3-(3-pyridinyl) -propyl]-1H-isoindole-2-acetamide hydrochloride dissolved in 200 ml of dimethylformamide was added 100 ml of 40% aqueous methylamine. The reaction mixture was stirred overnight, diluted with water, and extracted twice with dichloromethane. The combined organic layers were washed with water, dried with potassium carbonate, and evaporated to give an oil. The oil was converted to the dihydrochloride salt and crystallized from methanol ether to give 23.25 g of rac.-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridinyl) -propyl]propanamide dihydrochloride, mp 256°-260° C. The mother liquors afforded an additional 4.9 g, mp 256°-259° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:14]1[CH:19]=[CH:18][C:17]([C@H:20]([NH2:23])[CH2:21][OH:22])=[CH:16][CH:15]=1.Cl.[NH+]1C=CC=CC=1>COCCO.C(OCC)(=O)C>[OH:22][CH2:21][C@@H:20]([NH:23][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1cccc2c(Cl)ccnc12
Reactant: N[C@H](CO)c1ccccc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: COCCO
Product: N#Cc1cccc2c(N[C@H](CO)c3ccccc3)ccnc12
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A solution of 4-Chloro-quinoline-8-carbonitrile (200 mg, 1.1 mmol), (S)-Phenylglycinol (160 mg, 1.2 mmol), pyridinium hydrochloride (138 mg, 1.2 mmol) in 2-methoxyethanol (3.5 mL) was placed in a microwave 150° C., 50 Watts for 2 h. The solution was diluted with ethyl acetate and washed with brine solution. Purification by silica gel (20-80% ethyl acetate/heptane) afforded 4-((S)-2-Hydroxy-1-phenyl ethylamino)-quinoline-8-carbonitrile (320 mg, 33%) as a white solid. LCMS (ESI) 290 (M+H).
Reaction SMILES: C(OP([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:18][CH:19]([CH3:33])[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([C:9]([CH3:15])=[C:21]([CH2:20][CH:19]([CH3:33])[CH3:18])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:11])[CH3:14]
Reactant: CC(C)CC(=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=C(CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Ethyl 2-(diethylphosphono)propanoate (23.9 g.) was added to dry toluene (250 mls.) containing 80% sodium hydride in mineral oil (3.0 g.) at room temperature. The resultant mixture was heated to 50°-60° C. for 5 minutes and then cooled to -30° to -40° C. To the cooled mixture was added benzyl 4-methyl-2-oxopentanoate (20 g.) and the resulting mixture was allowed to warm to room temperature over a period of 1 hour. The toluene solution was washed with dilute citric acid (50 mls.), water (2×50 mls.) and then dried over anhydrous sodium sulfate. The toluene was removed by evaporation in vacuo to yield E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)butenoate as a mixture of isomers in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.CN(C=O)C.Cl.[NH2:30][OH:31].[OH-].[K+]>CO.[Cl-].[Na+].O.CO.O.O>[Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11](=[N:30][OH:31])[NH2:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: NC(=NO)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 107 mg, 0.28 mmol) was dissolved in dry MeOH (5 mL) and dry DMF (1 mL) to which were added hydroxylamine hydrochloride (0.50 g, 7.2 mmol) and potassium hydroxide (0.39 g, 7.0 mmol). The resulting suspension was stirred at room temperature for 16 h, then poured into brine (25 mL) and water (25 mL), and the resulting aqueous suspension extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a clear oil which was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a light tan solid which was recrystallized from MeOH/H2O to yield 81 mg (70%) of 4.33 as a light tan solid: mp dec >150 C; Rf 0.4 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.71 (s, 1H, D2O exch.), 8.47 (s, 1H), 7.97 (s, 1H), 5.95 (d, 1H), 5.78 (s, 2H, D2O exch.), 5.36-5.33 (m, 2H, D2O exch.), 5.23 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.14 (m, 1H), 3.96 (d, 1H), 3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 145.92, 132.24, 125.86, 125.78, 125.10, 123.92, 121.27, 114.85, 107.15, 88.61, 85.77, 71.24, 69.59, 61.09. HRMS (EI) m/z calcd. for C14H14Cl3N3O5 408.9999, found 408.9999. Anal calcd for C14H14Cl3N3O5: C, 40.95; H, 3.44; N, 10.23. Found: C, 40.89; H, 3.61; N, 10.08.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([O:16][Si](C)(C)C)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][CH:10]([C:9](=[O:16])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC=C(C=Cc1ccccc1)O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)CC(Br)C(=O)C=Cc1ccccc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 4.2 g of the product of Step C., 40 ml of tetrahydrofuran and 2.7 g of N-bromo-succinimide was cooled to 0° C. and stirred for one hour at this temperature, then brought to dryness. The residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) to obtain 1.9 g of the expected product. Thin layer chromatography; Rf=0.28 [eluant: hexane-ethyl acetate (8-2)].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)C>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Sodium hydride in mineral oil (60%, 7.92 g, 198.02 mmoles) was washed with hexanes then suspended in dimethylformamide (220 mL). The mixture was cooled to 0° C. Trimethyl phosphonoacetate (29.0 mL, 189.82 mmoles) was added dropwise to the stirred reaction mixture. After 20 min at 0° C., a solution of N-tert-butoxycarbonyl-4-piperidone (30.41 g, 152.62 mmoles) in dimethylformamide (80 mL) was added to the mixture dropwise. The reaction was stirred at room temperature for 3 h and then diluted with diethyl ether (650 mL). The mixture was washed once with water and the aqueous layer was extracted once with diethyl ether. The combined organic layers were washed 4 times with water and the aqueous phase was discarded. The organic phase was washed with brine and dried over magnesium sulfate, filtered, and concentrated to dryness. The title compound was obtained as a white solid in 92% yield. 1H-NMR (300 MHz, CDCl3): δ=5.68 (s, 1H), 3.66 (s, 3H), 3.40-3.51 (m, 4H), 2.90 (t, J=5.49, 2H), 2.25 (t, J=5.49, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[CH3:19])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:29]([Si:33]([CH3:41])([CH3:40])[O:34][CH2:35][CH2:36][CH2:37][O:38][NH2:39])([CH3:32])([CH3:31])[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.CCOCC>[C:29]([Si:33]([CH3:40])([CH3:41])[O:34][CH2:35][CH2:36][CH2:37][O:38][NH:39][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[CH3:19])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCCON
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(I)ccc1Nc1cc(F)ccc1C(=O)NOCCCO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a mixture of 4-fluoro-2-(4-iodo-2-methyl-phenylamino)benzoic acid (3.32 g, 8.95 mmol) in dichloromethane at ambient temperature was added diisopropylethylamine (2.82 mL, 16.2 mmol). To the resultant solution was added O-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-hydroxylamine (2.19 g, 10.65 mmol) and PyBOP. After 1.5 h of stirring, the solution was diluted with ether (100 mL) and was washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate and filtered, and concentrated in vacuo to obtain a gum. Chromatographed the gum using a gradient of 100% hexanes to 30% ethyl acetate in hexanes over 45 min. The solvent of the combined fractions was removed in vacuo to obtain a yellow gum. The gum was dried on a vacuum pump for c.a. 18 h which afforded N-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide as a solid. (4.06 g, 81% yield). 1H-NMR (400 MHz, CDCl3) δ 9.3 (br. s., 1H), 9.0 (br. s., 1H), 7.58 (s, 1H), 7.49 (dd, 1H, J=8.3, 1.95 Hz)), 7.36 (br. t., 1H, =5.71 Hz), 7.05 (d, 1H, J=8.3 Hz), 6.65 (dd, 1H, J=11.96, 2.44 Hz), 6.4 (br. t., J=7.1 Hz), 4.14 (t, 2H, J=5.61 Hz), 3.812 (t, 2H, J=5.62 Hz), 2.28 (s, 3H), 1.94 (p, 2H, J=5.86 Hz), 0.9 (s, 9H), 0.08 (s, 6H). 19F-NMR (376 MHz, CDCl3) δ −105.25. MS (AP+) 559.2 m/z, (AP−) 557.1 m/z.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=1.ClC(OCC)=O.CCN(CC)CC.[K+].[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30]C([O-])=O.[Mg+2].[Cl-].[Cl-]>CC#N.CCN(CC)CC>[CH2:36]([O:35][C:29](=[O:34])[CH2:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:4]2[CH:5]=[N:1][N:2]=[CH:3]2)[CH:7]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(-n2cnnc2)c1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1

Procedure:
Prepared from 3-[1,2,4]triazol-4-yl-benzoic acid [prepared by reaction of 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformate in acetic acid at 120° C.] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a white solid (5.74 g).
Reaction SMILES: C[O:2][C:3](=[O:19])/[C:4](/[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[CH:5]/[CH:6]([CH3:8])[CH3:7].[OH-].[Na+]>C(O)C>[CH3:18][S:15]([C:12]1[CH:11]=[CH:10][C:9](/[C:4](=[CH:5]\[CH:6]([CH3:8])[CH3:7])/[C:3]([OH:19])=[O:2])=[CH:14][CH:13]=1)(=[O:16])=[O:17]
Reactant: COC(=O)/C(=C/C(C)C)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)/C=C(/C(=O)O)c1ccc(S(C)(=O)=O)cc1
Temperature: 47.5 °C
Yield: 92 %

Procedure:
A solution of (E)-2-(4-(methanesulfonyl)-phenyl)-4-methyl-pentenoic acid methyl ester (1.83 g, 6.48 mmol) in ethanol (35 mL) was treated with a 1N aqueous sodium hydroxide solution (15 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (50 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×70 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-(4-(methanesulfonyl)-phenyl)-4-methyl-pentenoic acid (1.6 g, 92%) as a white solid: mp 179-182° C.; EI-HRMS m/e calcd for C13H16O4S (M+H)+269.0847, found 269.0858.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:9]([F:22])[CH:8]=1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[CH:8][C:9]=1[F:22])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
Add butyllithium (14.2 mL, 22.7 mmol) to a solution of 4-bromo-N-(tert-butoxycarbonyl)-2-fluoro-benzylamine (3 g, 9.9 mmol) in diethyl ether (105 mL) at −78° C. under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (1.086 g, 1.4 mL, 10.8 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.179 g, 37%).