Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(O)ccc1F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylene chloride (96 mL) was cooled to 0° C. in an ice bath. Triethylamine (4.9 mL, 35 mmol) was introduced to the solution followed by dropwise addition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with methylene chloride and washed with 0.5 N HCl, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.00 (m, 1H), 6.87 (m, 2H), 2.29 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[O:24])[C:5]1=[O:32])(=[O:44])[CH3:43]
Reactant: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCOC(C)C)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(1-methylethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.021 g, 0.046 mmol) and diisopropyl ethylamine (0.04 mL, 0.23 mmol) in DMF (5 mL) under nitrogen was treated with acetic anhydride (0.0046 mL, 0.048 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was treated with 1 N NaHSO4. Extracted the mixture twice with EtOAc, combined the organics, dried over MgSO4, filtered and concentrated the filtrate. The residue was then triturated with Et2O, filtered, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.0 Hz, 6 H), 1.7 (s, 3 H), 3.3 (q, J=6.1, 2 H), 3.5 (m, 3 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (t, J=6.5 Hz, 2 H), 7.1 (m, 2 H), 7.4 (ddd, J=12.1, 5.5, 3.2 Hz, 2 H), 8.0 (d, J=6.0 Hz, 1 H), 8.2 (d, J=1.3 Hz, 1 H), 8.5 (d, J=1.5 Hz, 1 H), 10.4 (t, J=5.1 Hz, 1 H), 17.1 (s, 1 H); ES+ MS: 485 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-c1cc(Cc2nnnn2Cc2ccccc2)ccc1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1cc(Cc2nnnn2Cc2ccccc2)ccc1C(=O)O

Procedure:
A 50 mL round-bottom flask was charged with 4-(l-benzyltetrazol-5-ylmethyi)-2-(2-methylphenyl)benzoate (A) (205.8 mg, 0.52 mmol) and ethanol (10 mL). 4 N sodium hydroxide (1.1 mL, 4.16 mmol) was added. The reaction was refluxed for 2 h and then cooled. The solvent was removed under vacuum and then diluted with water. The reaction was extracted with Et2O (3×10 mL). The pH of the aqueous layer was adjusted to 2 with 1 M H3PO4. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. Yield: 205.1 mg, white solid. 1H NMR (δ, CDCl3): 8.0 (2H), 7.0-7.4 (10H), 5.7 (2H), 4.3 (2H), 2.0 (3H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]([C:17]1([C:48]([OH:50])=[O:49])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:51]([O:57][CH2:58]Cl)(=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53].O>CN(C)C(=O)C>[CH3:53][C:52]([CH3:55])([CH3:54])[C:51]([O:57][CH2:58][O:49][C:48]([C:17]1([C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[C:37]([F:47])[CH:36]=4)[O:32][N:31]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:50])=[O:56]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium carbonate (0.125 g, 0.0012 mol) is added to a solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}piperidine-4,4-dicarboxylic acid mono benzyl ester (0.35 g, 0.00059 mol) in N,N-dimethylacetamide (3.5 mL). The reaction mixture is stirred for 30 minutes at room temperature. Chloromethyl pivalate (0.187 g, 0.0012 mol) is added to the reaction mixture which is then heated at 65° C. for 4 hrs. The reaction mixture is treated with demineralized water (5 mL) and extracted in ethyl acetate (2×5 mL). Sodium chloride (0.25 g) is added to the ethyl acetate layer and stirred for 15 minutes. Demineralized water (5 mL) is added to the ethyl acetate layer and the layers are separated. The ethyl acetate layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 70:30) to furnish 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (2,2-dimethylpropanoyloxymethyl) ester.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][NH:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8].Cl[CH2:17][C:18]([N:20]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH2:3][CH2:4][N:5]([CH2:17][C:18]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:19])[CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C)NCC1
Reactant: O=C(CCl)N(Cc1ccccc1F)C1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)C(c2ccccc2C)N(CC(=O)N(Cc2ccccc2F)C2Cc3ccccc3C2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4,5-dimethyl-6-o-tolyl-1,2,3,6-tetrahydro-pyridine (170 mg; 0.85 mmol), 2-chloro-N-(2-fluoro-benzyl)-N-indan-2-yl-acetamide (403 mg; 1.27 mmol) and K2CO3 (587 mg; 4.25 mmol), and acetonitrile (20 ml) is stirred at 80° C. for 20 hours. The reaction mixture is filtered, the insolubles are washed with ethyl acetate, and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography over silica gel (elution with hexanes/ethyl acetate 3:1) to give the product (Compound 13) as an oil. LC-MS [MH+] 483.25, RT=2.69 min.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=O)[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)(=O)C>CCCCCCC>[C:2]1([C:1]2[S:32][C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccccc2)s1
Yield: 75.1 %

Procedure:
To a solution of (S)-tert-butyl (1-(2-benzoylhydrazinyl)-1-oxopropan-2-yl)carbamate (155 mg, 0.5 mmol, 1.0 equv. in 5 ml of THF) was added Lawesson's reagent (36.4 mg, 0.5 mmol, 1.0 equv.) the reaction mixture was stirred at reflux for 3 hours, the reaction mixture was filtered and the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) to provide (S)-tert-butyl (1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (114.6 mg, white solid) in 70.7% yield. 1H NMR (400 MHz, CD2Cl2) δ 7.94-7.72 (m, 2H), 7.52-7.26 (m, 3H), 5.59 (b, 1H), 5.11 (b, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.34 (s, 9H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[CH2:30]([OH:33])[C:31]#[CH:32].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([C:32]#[C:31][CH2:30][OH:33])[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: C#CCO
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1sc(C#CCO)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (150 mg, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (11 mg, 0.015 mmol), copper(I)iodide (5 mg, 0.024 mmol) in THF (1 mL) was added propargyl alcohol (35 μL, 0.6 mmol) then triethylamine (1 mL) under an atmosphere of nitrogen. The resultant mixture was stirred at 50° C. for 3 hours before being cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed with brine, dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica eluting with 80% ethyl acetate in cyclohexane to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol-5-yl]-amide as a yellow solid (112 mg, 78%). LCMS (Method 3) [M+H]+=476.2, RT=3.19 min.
Reaction SMILES: [Cl:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:4]([CH2:11][CH3:12])[N:3]=1.[OH-].[NH4+:14]>O1CCCC1>[Cl:1][C:2]1[C:6]([S:7]([NH2:14])(=[O:9])=[O:8])=[CH:5][N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: [NH4+]
Reactant: CCn1cc(S(=O)(=O)Cl)c(Cl)n1
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(S(N)(=O)=O)c(Cl)n1

Procedure:
To a solution of 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (0.5 g, 2.2 mmol, the product of Step D) in tetrahydrofuran (20 mL) was added 30% ammonium hydroxide (3.0 mL, 24 mmol) dropwise. The reaction mixture was heated to boiling with a heat gun and then stirred for 30 min Tetrahydrofuran was removed under reduced pressure, water (50 mL) was added, the reaction mixture was extracted into ethyl acetate (2×100 mL). The ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure to afford a solid. The solid was washed with hexane, and dried to afford 282 mg of the title compound. 1H NMR (CDCl3) δ 7.84 (s, 1H), 4.94 (br s, 1H), 4.15 (q, 2H), 1.51 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)[OH:6].[H-].[Na+].[F:15][C:16]([S:19](O)(=[O:21])=[O:20])([F:18])[F:17]>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[O:6][S:19]([C:16]([F:18])([F:17])[F:15])(=[O:21])=[O:20]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: O=S(=O)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an inert atmosphere, a stirred solution of 3-methylsalicylic acid methyl ester (9.96 g) in dichloromethane (150 mL) cooled in an ice bath, was treated portionwise with 55% sodium hydride dispersion in mineral oil (3.0 g). The mixture was stirred at 0° C. for 15 minutes, then trifluoromethyl sulfonic acid (18.65 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction was allowed to proceed for an additional hour. Water (75 mL) was added and the phases were separated. The organic layer was washed in turn with 10% potassium carbonate (75 mL) and with brine. The dried (Na2SO4) organic layer was evaporated and the resulting amber oil was purified by HPLC (diethyl ether-hexane; 1:4) to yield 14.3 g of 3-methyl-2-(trifluoromethylsulfonyloxy)benzoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:5]([CH:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC1(C)CC1C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
2,2-Dimethylcyclopropanecarboxylic acid (0.992 g, 8.69 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (2.21 g, 8.69 mmol) and triethylamine (2.20 g, 21.7 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1 g, 4.35 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added. The mixture was filtered, and the solid rinsed with water and dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide (672 mg, 47.4% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg, 1.9 mmol), aniline (350 mg, 3.8 mmol) and p-toluenesulfonic acid (catalytic) in toluene (15 mL) was heated at reflux for 16 h with a Dean-Stark trap in place. The reaction was cooled, concentrated, and the imine was purified by flash column chromatography on silica (gradient of 5% to 50% ethyl acetate/hexanes). The imine was dissolved in methanol (10 mL) and sodium borohydride (140 mg, 3.8 mmol) was added portionwise. The reaction was stirred for 30 min and quenched with water, concentrated, and diluted with ethyl actetate. The organic phase was separated, absorbed onto diatomaceous earth and purified by flash column chromatography on silica (gradient of 2% to 20% ethyl acetate/hexanes) to provide 6-bromo-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. 1H-NMR (DMSO-d6): δ 8.04 (s, 1H), 7.61 (s, 1H), 7.25-7.21 (m, 4H), 6.80-6.72 (m, 3H), 4.84-4.78 (m, 1H), 3.86-3.82 (m, 1H), 2.27-2.21 (m, 2H), 2.08-2.00 (m, 1H), 1.89-1.78 (m, 3H). The oil was dissolved in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 6-bromo-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (352 mg, 51%) as a yellow solid. 1H-NMR (DMSO-d6): δ 11.12 (s, 1H), 7.58 (s, 1H), 7.26 (d, 1H), 7.15-7.13 (m, 3H), 6.88-6.78 (m, 2H), 6.72-6.64 (m, 1H), 4.82-4.79 (m, 1H), 2.69-2.45 (m, 2H), 1.96-1.90 (m, 2H), 1.83-1.73 (m, 2H); MS m/z (M−1) 339, 341.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]([CH2:10][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13][CH2:12]1)[C:7]([OH:9])=O.[O:25]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:25]1[C:29]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:7](=[O:9])[C:6](=[O:5])[CH2:10][C:11]3([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:22])([F:23])[F:24])[CH2:14][CH2:13][CH2:12]3)=[CH:34][CH:35]=2)=[CH:28][N:27]=[CH:26]1
Reactant: O=C(O)C(=O)CC1(c2ccccc2C(F)(F)F)CCC1
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2cnco2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
0.052 ml of thionyl chloride was added to a solution of 0.1 g of 2-Oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionic acid in 2 ml of dimethyl acetamide at −5° C., and stirred for 30 min at −5° C. Then 56 mg of 4-oxazol-5-yl-phenylamine was added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 10%-20%) to yield 63 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:15][CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:15](\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1ccc(F)cc1
Yield: 99 %

Procedure:
4-Fluorobenzaldehyde (12 g, 97 mmol) was dissolved in toluene (500 mL). (Carboethoxyethylidene)triphenylphosphorane (42 g, 116 mmol) was added and the mixture was heated to reflux until the starting material was consumed. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo. The remaining residue was dissolved in ether, and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (20 g, 99% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 7.64 (s, 1H), 7.38 (dd, J=8.65, 5.59 Hz, 2H), 7.08 (t, J=8.65 Hz, 2H), 4.27 (q, J=7.12 Hz, 2H), 2.10 (d, J=1.36 Hz, 3H), 1.27-1.38 (m, 3H). MS (DCI+) 209 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:23]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([N:23]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCCCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
108 mg of compound 7 was obtained in a similar manner to those described in the Examples 1 and 2 using 580 mg of ethyl 4-(2-aminophenoxy)butyrate and 366 mg of 3-(1-hexylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([OH:32])=O)[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].[NH2:35][C:36]1[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:34])[NH:20][C:21](=[O:33])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([NH:35][C:36]5[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[NH:38][N:37]=5)=[O:32])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: Nc1n[nH]c(C(F)(F)F)n1
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)Nc3n[nH]c(C(F)(F)F)n3)co2)c(=O)[nH]c1=S

Procedure:
A solution of the product of example 2 step (iii) (0.34 g), 4-(dimethylamino)pyridine (0.34 g), 3-amino-5-trifluoromethyl-1,2,4-triazole (J. Gen. Chem. USSR (Engl. Transl.) 1983, vol53, part 7, p1514) (0.42 g) and N,N-diisopropylethylamine (1.46 ml) in N,N-dimethylformamide (6 ml) was treated with bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (1.3 g). After 2 hours the solution was quenched with aqueous tartaric acid. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. The product was triturated with ethyl acetate/isohexane and the solid collected.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=[N:2][OH:3])[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of hydroxylamine hydrochloride (19 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (65 mg, 80%) was a white foam: EI-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202. found 451.1206.