Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][C:3]=1[Br:29].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37](O)=[O:38])[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([CH2:6][C@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:4][C:3]=2[Br:29])=[O:38])[N:35]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
To a solution of 81 mg (0.18 mmol) of tert-butyl (2R,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-80b) and (2-amino-1,3-thiazol-4-yl)acetic acid (45 mg, 0.18 mmol) in 2.0 mL anhydrous DMF was added HOBt (31 mg, 0.23 mmol) followed by EDC (45 mg) and DIEA (0.16 mL, 0.88 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by Gilson reverse phase HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA bufferto afforded the product (75 mg, 81%). m/z (ES) 601(M)+ and 603 (M+2)+, also 623 (MNa)+ and 625 (MNa+2)+.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[N+:8]([O-:11])(O)=[O:9].[CH2:12]=[CH:13][CH:14]=[CH:15][CH2:16][CH3:17]>>[N+:8]([CH2:12][CH:13]=[CH:14][CH:15]([O:4][C:1](=[O:3])[CH3:2])[CH2:16][CH3:17])([O-:11])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Reactant: C=CC=CCC
Product: CCC(C=CC[N+](=O)[O-])OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 166 ml. of acetic anhydride was added 90% nitric acid (27.7 g.) under cooling at 25° C. over a 45 minute period. After an additional 5 minutes of stirring 20 g. of 1,3-hexadiene was added dropwise at 25° C. over 1 hour. Ice cooling was employed as required. The reaction was completed by stirring the mixture for an additional hour, followed by quenching in ice and water. Extraction with methylenechloride, washing with water, drying of the organic layers over anhydrous sodium sulfate and evaporation of the solvent and excess acetic anhydride resulted in 47.0 g. of a crude reaction product. Column chromatography and careful bulb to bulb distillation (oven 120° C., 0.5 mmHg) yielded actic acid (1-nitro-2-hexen-4-yl)ester.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH:19][C:20]1[NH:21][CH2:22][CH2:23][N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[BrH:1].[CH2:12]([N:19]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4])[C:20]1[NH:24][CH2:23][CH2:22][N:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CNC2=NCCN2)cc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(C)=O
Product: Br
Product: O=C(CN(Cc1ccccc1)C1=NCCN1)c1ccc(Br)cc1
Reaction time: 48 h

Procedure:
To a stirred solution of 13.9 parts of 2.4'-dibromoacetophenone in 120 parts of acetone are added portionwise 8.75 parts of 2-(N-benzylamino)-2-imidazoline. Upon completion, stirring is continued for 2 days at room temperature. The precipitated product is filtered off, washed with acetone, dried and crystallized from ethanol, yielding 2-[N-benzyl-N-(2-imidazolin-2-yl)amino]-4'-bromo-acetophenone hydrobromide, m.p. 262.9°C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.Cl>ClCCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1)=[O:5]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#CC1(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (100 mg, 0.205 mmol) in DCE (10.0 mL) at RT was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) (58.9 mg, 0.307 mmol), 1-amino-1-cyclopropanecarbonitrile hydrochloride (24.3 mg, 0.296 mmol), DMAP (catalytic) and TEA (22.79 mg, 0.225 mmol). The resulting reaction mixture was stirred at RT for 18 h. To the reaction mixture was added EtOAc (50 mL) and 0.1N HCl (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with aq NaHCO3 (1×), dried (MgSO4), filtered and concentrated under reduce pressure to give an oil. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 35% EtOAc in hexanes) afforded the title compound as a white solid (13 mg, 11.5%). Characterization data for this molecule is listed in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:33][C:34]([CH3:39])([CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:41][CH:42]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
Methyl 3-[N-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (3.77 g, 6.27 mmol) from Step D of Example 1, was dissolved in 75 mL of dry CH2Cl2 and the solution was charged with 6.27 g (47.0 mmol) of AlCl3 and the mixture was stirred at RT, under Ar, for 1.75 hours. The reaction was then quenched by the addition of 0.5N Na, K tartrate (150 mL) and the resulting mixture was extracted with EtOAc (3×). The organic extracts were washed with 0.5N Na, K tartrate (1×) and with brine (1×), and dried (MgSO4). Filtration and removal of-solvents provided a brown oily residue which was chromatographed on silica gel using EtOAc-hexane (1:3) to give the title compound.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].C[O-].[Na+].[CH2:15]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]=[C:4]2[CH:5]3[C:8]([CH3:10])([CH3:9])[C:1]([CH3:11])([CH2:7][CH2:6]3)[C:2]2=[O:3])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1

Procedure:
A solution of 100 millimols (15.2 g) of camphor in 250 ml of toluene is heated for 1 hour at the boil with 100 mmols (5.4 g) of sodium methylate. After cooling, 100 mmols (17.8 g) of p-butoxybenzaldehyde are introduced and the mixture is heated at the reflux temperature for 4 hours. The reaction mixture is cooled and 50 ml of water are then added; the toluene phase is separated off, washed with water, dried over sodium sulphate and concentrated to dryness. The solid residue is crystallised from aqueous isopropanol. After drying, 12 g of a white owder, which melts at 62°, are collected.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH:5]=[N:6][NH:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10](F)[C:9]=1[F:17].O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[H-].[Na+].O1CCC[CH2:33]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH:5]=[N:6][NH:7][C:8]1[C:9]([F:17])=[C:10]([O:27][CH2:26][CH2:25][N:24]2[CH2:29][CH2:28][CH2:33][CH2:22][CH2:23]2)[N:11]=[C:12]([F:15])[C:13]=1[F:14]
Reactant: OCCN1CCOCC1
Reactant: C1CCOC1
Reactant: Cc1cccc(C=NNc2c(F)c(F)nc(F)c2F)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(C=NNc2c(F)c(F)nc(OCCN3CCCCC3)c2F)c1

Procedure:
N-(3-methyl-benzylidene)-N′-(2,3,5,6-tetrafluoro-pyridin-4-yl)-hydrazine (2.2 g; 7.8 mmol) was dissolved in tetrahydrofuran (100 mL) and to the solution was added 4-(2-hydroxyethyl)-morpholine (1.3 g; 10 mmol) followed by sodium hydride (480 mg; 20 mmol). The solution was stirred at reflux for 24 hours. The solvent was then evaporated, and the solid was purified by column chromatography to give N-(3-methyl-benzylidene)-N′-[2,3,5-trifluoro-6-(2-piperidin-1-yl-ethoxy)-pyridin-4-yl]-hydrazine (830 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5][NH:24][C@@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1cc(CN[C@H]2CCCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
3-Fluoro-5-(trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18](=[CH2:21])[CH2:19]O>>[CH3:19][C:18](=[CH2:17])[CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: C=C(C)CO
Product: C=C(C)COC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-methylprop-2-en-1-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([N:13]2[C:17]([C:18]([OH:20])=O)=[CH:16][C:15](=[O:21])[NH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:32]([C:33](O)=[O:34])[C:31]=1[NH2:40]>C(#N)C.O>[Cl:39][C:37]1[CH:38]=[C:30]([Cl:29])[C:31]2[N:40]=[C:18]([C:17]3[N:13]([C:8]4[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][N:9]=4)[N:14]=[C:15]([O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=3)[O:20][C:33](=[O:34])[C:32]=2[CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: O=C(O)c1cc(=O)[nH]n1-c1ncccc1Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cc(-c2nc3c(Cl)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methanesulfonyl chloride (0.14 mL, 1.75 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylic acid (i.e. the product of Step C) (0.4 g, 1.67 mmol) and triethylamine (0.23 mL, 1.67 mmol) in acetonitrile (3 mL) at 0-5° C. The reaction temperature was then maintained at about 0° C. throughout the addition. After stirring for 10 minutes, 3,5-dichloroanthranilic acid (Aldrich, 0.34 g, 1.67 mmol) was added and stirring was continued for an additional 5 minutes. A solution of triethylamine (0.47 mL, 3.33 mmol) in acetonitrile (3 mL) was then added dropwise, and the reaction mixture stirred 40 minutes, followed by the addition of methanesulfonyl chloride (0.14 mL, 1.75 mmol). The reaction mixture was then warmed to room temperature and stirred overnight. Approximately 50 mL of water was then added followed by extraction with ethyl acetate (3×30 mL). The combined ethyl acetate phase was washed with water (1×20 mL) followed by brine (1×20 mL), dried (MgSO4) and concentrated to yield 0.8 g of a crude yellow solid. Chromatography on silica gel using hexanes/ethyl acetate as eluent resulted in isolation of 0.11 g of the title compound as a yellow solid.
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:34]=[C:32]([NH:31][C:27]3[CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=[CH:29][CH:28]=3)[N:33]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)Nc1cccc(CO)c1
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Product: OCc1cccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccccc2F)C3)c1

Procedure:
This was synthesized by using general procedure 6 except that (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one reacted with 1-(3-(hydroxymethyl)phenyl)guanidine to give (R)-(3-(6-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenyl)methanol M.p.=158-159° C. 1H NMR 400 MHz (DMSO-d6) δ 9.57 (s, 1 H), 8.41-8.39 (m, 1 H), 8.32 (s, 1 H), 7.92 (s, 1 H), 7.70-7.68 (m, 1 H), 7.53-7.45 (m, 2 H), 7.29-7.21 (m, 3 H), 7.08-7.02 (m, 2 H), 6.91-6.89 (d, 1 H), 6.81-6.77 (m, 1 H), 5.19 (t, J=6.0 Hz, 1 H), 4.67 (t, J=6.8 Hz, 1 H), 4.52 (d, J=5.2 Hz, 2H), 3.22-3.02 (m, 2 H). LCMS m/e 398 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[CH3:14][CH:15]([CH3:18])[C:16]#[CH:17]>C(N(CC)CC)C.[Cu]I.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>[NH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[C:17]#[C:16][CH:15]([CH3:18])[CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CCOC(=O)c1ccc(I)c(N)c1
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl3-amino-4-iodobenzoate (Compound 31, 6.87 g, 23.1 mmol) in triethylamine (50 ml) at 25° C. under argon then added CuI (22 mg, 1.16 mmol), Pd(PPh3)2Cl2 (82 mg, 1.16 mmol), and 3-methyl-1-butyne ( 3.18 g, 46.2 mmol). The reaction was stirred for 20 h at 25° C., filtered off brown solid, and then rinsed solid with EtOAc, organic layer was concentrated in vacuo. The residue was purified by chromatography on silica gel (0→25% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:11]([C:13]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[F:14])=[O:12])([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].[F-:23].[K+].S(O[CH2:32][CH3:33])(OCC)(=O)=O.[OH-].[K+]>O.COCCOC>[C:13]([C:11]([C:1]([C:3]([F:6])([F:5])[F:4])([C:7]([F:10])([F:9])[F:8])[F:2])([O:12][CH2:32][CH3:33])[F:23])([C:15]([F:16])([F:17])[F:18])([C:19]([F:20])([F:21])[F:22])[F:14]
Reactant: CCOS(=O)(=O)OCC
Reactant: [F-]
Reactant: O=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCOC(F)(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 52 °C
Reaction time: 89 h
Yield: 6.1 %

Procedure:
302 grams (0.83 mole) of a ketone mixture of 96.0 percent (CF3)2CFC(O)CF(CF3)2 and 4.0 percent CF3CF2CFC(O)CF(CF3)2, 300 mL anhydrous 1,2-dimethoxyethane, 59.5 grams (1.02 mole) potassium fluoride, 11.1 grams Adogen™ 464 phase transfer catalyst, and 174 grams (1.12 mole) diethyl sulfate were combined in a 2 L flask and heated with stirring to 52° C. for 89 hours. At the end of the 89 hours, the flask was cooled to room temperature, and 230 grams of 45 percent potassium hydroxide and 95 grams of water were added. The resulting mixture was distilled azeotropically using a Dean Stark trap, from which the resulting lower fluorochemical phase was separated during the distillation. The fluorochemical phase was washed twice with an equal volume of water and dried over magnesium sulfate. 53.0 grams of material resulted, with a purity of 37.6 percent (CF3)2CFCF(OC2H5)CF(CF3)2 (yield of 6.1 percent; structure confirmed by GCMS).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.COC(=O)CC1C2C(=CC=C(Cl)C=2)N[C:29]=1[C:38]([C:40]1[NH:41][CH:42]=[CH:43][N:44]=1)=[O:39]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:38]([C:40]1[NH:41][CH:42]=[CH:43][N:44]=1)=[O:39]
Reactant: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2ccc(Cl)cc12
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ncc[nH]2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (Step 1 of Example 8, Method A) and 2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (Preparation is described in step 1 of Example 245).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.Cl>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)Cc1ccc(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]([O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide from step 4 in a mixture of MeOH/THF (20 mL, 1:1) was added 1 N NaOH. The reaction mixture was stirred at room temperature overnight. IN HCl was added to acidify the solution to pH 4. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried and concentrated. The residue was then purified by reverse phase chromatography to afford the product (1.4 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][N:36]2[CH2:40][C@@H:39]([C:41]3[CH:52]=[CH:51][C:44]4[O:45][C:46]([CH3:50])([CH3:49])[O:47][CH2:48][C:43]=4[CH:42]=3)[O:38][C:37]2=[O:53])=[CH:30][CH:29]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:49][C:46]1([CH3:50])[O:45][C:44]2[CH:51]=[CH:52][C:41]([C@H:39]3[O:38][C:37](=[O:53])[N:36]([CH2:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][O:15][CH2:14][C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[CH:9]=5)=[CH:33][CH:32]=4)[CH2:40]3)=[CH:42][C:43]=2[CH2:48][O:47]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Reactant: C[Si](C)(C)CCOCOc1cccc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(OCOCC[Si](C)(C)C)c5)cc4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of (3-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)methanol in DMF (5 ml) under nitrogen was treated with sodium hydride (18 mg, 60% in oil) and the mixture was stirred at 20° C. for 15 min. 2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate (150 mg) was added and the mixture was stirred at 20° C. for 20 h. Phosphate buffer solution (20 ml, pH6.5) was added and the mixture was extracted with EtOAc (30 ml). The organic extract was washed with water (2×20 ml) and dried (Na2SO4). The solvent was evaporated in vacuo to give a residue which was purified by chromatography on flash silica gel. Elution with EtOAc-petroleum ether 40°-60° (1:1) gave the title compound (90 mg) LCMS RT=4.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]1
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 9 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), 4-acetamidopiperidine (43 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, MeOH, 1:1:0.05) to furnish the title compound as white solid (7 mg, 9%), LC-MS (ESI, 3.5 min) Rt 2.25 min; m/z (ESI) C12H16Cl2N3O requires 288.0665 found [M+H]+ 288.0664; HPLC Rt 5.98 min, 100%.
Reaction SMILES: C1(C)C=CC(S[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)([CH3:11])[C:9]#[N:10])=CC=1.O.CCOCC>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:18]([C:14]1[CH:13]=[C:12]([CH:8]([CH3:11])[C:9]#[N:10])[CH:17]=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(SC(C)(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 91.6 %

Procedure:
417 mg of alpha-(p-tolylthio)-alpha-(m-phenoxyphenyl)propionitrile was dissolved in 4 ml of acetic acid. Zinc powder (370 mg) and 25 mg of anhydrous copper sulfate were added. The mixture was heated under reflux for 1 hour with stirring. After the cooling, 20 ml of water and 20 ml of ether were added. The insoluble matter was separated by filtration. Sodium carbonate (5 g) was added to the filtrate to neutralize the acetic acid, followed by extraction with ether (15 ml×4 times). The extract was washed with 30 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 247 mg (yield 92%) of alpha-(m-phenoxyphenyl)propionitrile as an oil. A sample for elemental analysis was prepared by subjecting the oil to bulb-to-bulb distillation [149°-154° C. (bath temperature)/1 torr].