Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C1COCC1.[Br-].[Mg+2].[Br-].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Mg+2].[Br-]>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:4]=1)=[O:7]
Reactant: COc1ccccc1
Reactant: CNc1nccc(-c2cccnc2Oc2cc(C(=O)Cl)ccc2C)n1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1nccc(-c2cccnc2Oc2cc(C(=O)c3ccccc3OC)ccc2C)n1
Temperature: -78 °C

Procedure:
To 4-methyl-3-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride (50 mg, 0.14 mmol) in a flame dried, round-bottom flask under nitrogen and cooled to −78° C. was added 4 ml of THF, 2 ml methylene chloride and magnesium-bromide-2-methoxy-benzene in THF (0.3 ml, 0.6 mmol). After addition of the magnesium-bromide, the −78° C. dry ice bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methylene chloride and brine. The organic layers were combined, dried with sodium sulfate and filtered. The solvent was removed under vacuum and the product was purified via preparative HPLC (Gilson). MS m/z=427 [M+H]+. Calc'd for C25H22N4O3: 426.48.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[CH3:16]C(C)([O-])C.CI>CS(C)=O>[CH3:16][N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1

Procedure:
Prepared by reacting 4-(4-nitro-phenyl)-imidazole in DMSO with potassium-tert.butoxide at 0° C. and then with methyliodide at 20-25° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Yield: 71.6 %

Procedure:
To a solution of potassium permanganate (3.05 g) in water (100 ml) was added to a solution of 3,4-dimethoxy-5-nitrobenzaldehyde (2.7 g) in acetone (80 ml). The mixture was then stirred at 20° for 18h whereupon the acetone was evaporated and the residue acidified (2N HCl) and was then decolourised by the addition of sodium metabisulphite sodium. The mixture was then extracted with ethyl acetate (3×200 ml) and the dried extracts evaporated to give the title compound as a colourless solid (2.08 g) m.p. 197°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:31][O:32][C:33](=[O:37])[CH2:34][N:35]([CH2:7][C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C:12]([N:14]1[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:16][C@H:15]1[CH3:29])=[O:13])[CH3:36]
Reactant: CNCC(=O)OC
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN(C)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C

Procedure:
To a solution of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.10 g, 0.24 mmol) in methanol (2.5 ml) was added sarcosine methyl ester hydrochloride salt (0.10 g, 0.72 mmol) followed by sodium triacetoxyborohydride (0.155 g, 0.73 mmol). After 15 hours the solvent was removed and the resultant solid taken up in methylene chloride. After washing with pH 7 phosphate buffer (0.05 M) and saturated aqueous sodium chloride the organic layer was dried over magnesium sulfate. After filtration and concentration the title compound was isolated by chromatography on silica gel (0.051 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccncc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1NN=C(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
3-Bromo-4-methyl-pyridine (1.0 g, 5.81 mmol) in 5 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (335 mg, 0.58 mmol), and sodium tert-butoxide (840 mg, 8.72 mmol). The mixture was degassed with argon for 15 minutes. Added Pd(II)(OAc)2 (130 mg, 0.58 mmol) and stirred at 90° C. for 14 hours. Extracted using EtOAc/H2O (3×200 mL EtOAc, lx 100 mL H2O, 1×100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 10-50% EtOAc/Hexane) to afford 3-(2-(diphenylmethylene)hydrazinyl)-4-methylpyridine (1.00 g, 3.48 mmol, 60%). 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.97 (d, 1H), 7.67-7.52 (m, 6H), 7.45-7.36 (m, 5H), 7.06 (d, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 488 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 204 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.44 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.24 ml), water (0.24 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. The resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-3-ethyl-4-guanidinoimino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 27) (0.6 g) as colorless crystals.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]3[CH2:12][C@H:13]4[CH2:26][C@H:14]4[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:17]=2)=[O:9])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[O:32]=[S:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]3[CH2:12][C@H:13]4[CH2:26][C@H:14]4[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:17]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1CCSCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Solvent: ClCCl
Product: O=C(NC1CCS(=O)CC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reaction time: 1 h
Yield: 14.5 %

Procedure:
A solution of (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (tetrahydro-thiopyran-4-yl)-amide (0.014 g, 0.037 mmol) in anhydrous DCM (0.5 mL) was cooled to 0° C. on an ice bath. 3-Chlorobenzoperoxoic acid (7.08 mg, 0.041 mmol) in DCM (0.5 mL) was added drop wise and the reaction was stirred for 1 hour. The reaction mixture was extracted with DCM/water and NaHCO3. The organic phase was concentrated and the residue was purified by HPLC to provide the title compound (2.1 mg) as a white solid. LCMS m/z=392.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:21]([NH2:22])[C:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[CH:4]2
Reactant: Nc1ccc(F)cc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12](C(OC(C)(C)C)=O)[C@@:11]([CH2:21][OH:22])([CH3:20])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[NH:12][C@@:11]([CH2:21][OH:22])([CH3:20])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cncc(F)c2)CC[C@@]1(C)CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (200 mg, 0.644 mmol) in DCM (5 mL) was added 4M HCl in dioxane (1.61 mL, 6.44 mmol). The reaction was stirred at ambient temperature for 16 hours and then concentrated to afford ((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanol hydrochloride (130 mg, 96% yield). MS (apci) m/z=211.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:24]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([O:31][C:32]1[CH:37]=[C:36]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3cccc(OCc4ccccc4)c3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 150 mmol), 3-Benzyloxyphenylboronic Acid (70 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 0.5 microliters of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 60-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (9.7 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 5.21 (s, 2 H) 6.59 (d, J=2.27 Hz, 1 H) 7.27-7.32 (m, 1 H) 7.36 (d, J=7.33 Hz, 1 H) 7.39-7.44 (m, 1 H) 7.49-7.54 (m, 2 H) 7.49-7.57 (m, 1 H) 7.54-7.59 (m, 1 H) 7.60-7.67 (m, 3 H) 7.75-7.79 (m, 1 H) 8.01-8.06 (m, 3 H) 8.19 (d, J=2.27 Hz, 1 H) 11.26 (s, 1 H). ESI-MS: m/z 479.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:12][C:11]1[O:18][C:16](=[O:17])/[C:15](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)/[N:14]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CSc1ccc(/C=C2\N=C(C)OC2=O)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
4-(Methylsulfanyl)benzaldehyde (31.8 g), (acetylamino)acetic acid (24.5 g) and acetic anhydride (35 ml) were combined, and then sodium acetate (8.57 g) was added to the suspension at room temperature under nitrogen atmosphere. The reaction mixture was refluxed for 3.5 hours. After cooled to room temperature, the mixture was poured into ice-water and ethyl acetate with stirring, and filtered in vacuo. The filtrate was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue and the previously obtained solid were combined, and the mixture was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether to give (4Z)-2-methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one (17.8 g) as a brown solid.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Br:12])[CH:6]=1.[C:13](=[O:15])=[O:14].Cl>CCOCC.O>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1cc(F)cc(Br)c1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Magnesium turnings (1.97 g) and iodine (catalytic amount) were added to ether (150 ml), and 1,3-dibromo-5-fluorobenzene (19.6 g) in ether (20 ml) was added dropwise under nitrogen atmosphere at such a rate that gentle reflux occurred. The mixture was refluxed for 3 hours, and left to cool. Crushed dry ice was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and acidified with hydrochloric acid. The mixture was extracted with ether (200 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1), to thereby yield 9.37 g of the target compound (yield: 55.4%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCOCC1>[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][O:27][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
15.4 g of p-nitrobenzenesulphonyl chloride are added in portions at 20°-25° C. to a stirred suspension of 12.0 g of the alcohol from Example 8 in 35 ml of THF and 7.66 ml of N-methylmorpholine and stirred for 4.5 hours. The suspension is again treated with 0.77 ml of N-methylmorpholine and stirred at 22° C. for 4.5 hours. The mixture is treated with 70 ml of a 2% sodium bicarbonate solution, stirred for 1.5 hours, filtered, the residue is washed with water and ethanol and dried to give 21.4 g (94%) of 98.5 % p-nitrobenzenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148°-149.5° C., α!D20 : +10.0° (1% in acetone).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)(=O)C.C(O)C.[Fe]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([OH:12])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1cc(O)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.9 %

Procedure:
Iron powder (1.59 g, 28.5 mmol) was added slowly to a solution of 3-(methylthio)-4-nitrophenol (1.76 g, 9.5 mmol) in acetic acid (50 mL) and ethanol (5 mL). The mixture was stirred 17 hours at room temperature.v Then iron was removed with a magnet and the slurry mixture filtered. The filtrate was diluted in water (100 mL) and neutralised with a saturated solution of Na2CO3. The mixture was extracted with DCM, and the combined organic layer dried over Na2SO4. Then, the solvent was evaporated under vacuum to provide the title compound (780 mg, 53%) as a grey powder. 1H-NMR (δ, ppm, DMSO-d6): 2.29 (s, 3H, HMe), 4.48 (bs, 2H, NH2), 6.44 (d, 1H, Harom 5, J6-5=8.5 Hz), 6.54 (d, 1H, Harom 6, J6-5=8.5 Hz), 6.61 (s, 1H, Harom 2), 8.58 (broad s, 1H, OH). GC-MS (m/z): 155.09
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Cl[CH:24]([CH3:27])[C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH:24]([C:25]#[N:26])[CH3:27])=[O:8]
Reactant: CC(Cl)C#N
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OC(C)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem., 35:958 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by 2-chloropropionitrile (1.1 mL, 12.6 mmol). The mixture is stirred at room temperature for 1.5 hours then warmed to 82° C. for 3 hours. The reaction mixture is poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 853 mg, mp 127°-129° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28](Cl)=[O:29]>CCOCC>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1F
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 3-fluoro-4-hexadecylaminobenzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 3-fluoro-4-(hexadecylamino)benzoylpiperidine.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:18]([OH:21])(=O)[CH3:19]>>[O:21]=[C:18]1[C:19]2[C:8](=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:9][N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred mixture of phthalic dicarboxaldehyde (2.68 g, 20.0 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionic acid (4.78 g, 20.0 mmol) in glacial acetic acid (50 mL) under nitrogen was heated to reflux for 5 minutes. The reaction mixture was then allowed to cool to room temperature and was concentrated in vacuo to afford a yellow solid. The crude product was recrystallized twice from refluxing ethanol (150 mL). The resulting solid was then dried in vacuo (60° C., <1 mm) to afford 4.4 g (62%) of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid as a white solid: mp 193.5-194° C.; 1H NMR (DMSO-d6) δ12.40 (br s, 1H), 7.75-7.40 (m, 4H), 7.05-6.85 (m, 3H), 5.71 (m, 1H), 4.51 (d, J=17.7 Hz, 1H), 4.11 (d, J=17.7 Hz, 1H), 3.99 (m, 2H), 3.73 (s, 3H), 3.25-3.02 (m, 2H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ171.9, 166.9, 148.5, 147.9, 141.7, 132.2, 131.6, 131.4, 127.9, 123.5, 122.9, 119.3, 111.8, 63.7, 55.4, 51.2, 46.3, 36.8, 14.7; Anal. Calcd. for C20H21NO5. Theoretical: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.64; H, 5.97; N, 3.92.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([C:12]#[C:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH3:2].C(N(CC)CC)C>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Yield: 75.5 %

Procedure:
tert-Butyl 4-(4-((4-((3-(2-ethoxy-2-oxoethyl)pyrazin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I102) (I87 mg, 0.306 mmol) was dissolved in DMF (20 mL), triethylamine (0.1 mL) and a slurry of 10% Pd/C (0.100 g) in DMF (2 mL) was added. The mixture was purged with 3×vacuum/hydrogen cycles, and then stirred vigorously under a hydrogen atmosphere. After 17 hours the mixture was filtered through celite, and the celite washed with ethyl acetate (200 mL). The combined filtrates were washed with 1:1 water:saturated brine (4×100 mL), dried (sodium sulphate) and evaporated to give the title compound (I103) (142 mg, 76%) as a yellow oil; 1H NMR (400 MHz, d4-MeOD) δ 8.51 (d, J=0.6 Hz, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.20-7.13 (m, 2H), 4.21 (dd, J=11.4, 1.8 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.97 (s, 2H), 3.37 (s, 4H), 2.87 (br s), 2.70 (tt, J=11.9, 3.3 Hz, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.59 (ddd, J=25.6, 12.9, 4.4 Hz, 2H), 1.48 (s, 9H), 1.21 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.76 min; m/z 615.1 [M+H]+, 559.1 [M−tBu+2H]+, 515.1 [M−Boc+2H]+.