Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]#[N:11].[Cl-].[Cl:13][C:14](Cl)=[N+:15]([CH3:17])[CH3:16]>ClCCl>[C:10]([C:3]1[C:4]([CH:7]([CH3:9])[CH3:8])=[N:5][S:6][C:2]=1[N:1]=[C:14]([Cl:13])[N:15]([CH3:17])[CH3:16])#[N:11]
Reactant: CC(C)c1nsc(N)c1C#N
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Reaction time: 5 h
Yield: 61.3 %

Procedure:
A mixture of 142 g of 5-amino-4-cyano-3-isopropylisothiazole and 610 ml of dichloromethane was treated with 138 g of N-(dichloromethylene)-N,N-dimethylammonium chloride. The reaction mixture became warm during addition of the N-(dichloromethylene)-N,N-dimethylammonium chloride and was cooled in an ice-water bath to 31°. The reaction temperature was maintained at 30°-35° for one-half hour after addition was complete. The reaction mixture was then heated under reflux for an additional 44 hours. Nitrogen gas was then passed through the refluxing solution for 5 hours. The reaction mixture was allowed to cool to 15°-20° and filtered. The filter cake was washed with 150 ml of dichloromethane and dried to yield an unidentified white solid, mp 162°, which was discarded. The filtrate was washed with two 100-ml portions of saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to near dryness under reduced pressure. The residue was dissolved in 2250 ml of hot hexane, filtered hot and allowed to cool to room-temperature. The hexane solution was decanted from an oil which separated on cooling. The hexane solution was placed in a cooler overnight. The cold solution was filtered and dried to yield 133.7 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 68°-71°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13]Br>O1CCOCC1.N#N.ClC(Cl)C>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Cn1ccnc1N1CCOCC1
Agent: N#N
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: Cn1c(Br)cnc1N1CCOCC1
Temperature: 60 °C
Yield: 31 %

Procedure:
4-(1-Methyl-1H-imidazol-2-yl)-morpholine (Nagarajan, K. et al. Indian J. Chem. Sect. B, 21, 10, 1982, 949-952) (1.02 g, 6.08 mmol) was dissolved in 35 mL of 1,4-dioxane under and N2 atmosphere. The mixture was heated to 60° C. and a solution of 0.34 mL (6.4 mmol) of Br2 in 10 mL of dichloroethane was added slowly. The mixture was heated for 1 h, then cooled. The mixture was concentrated and the residue was partitioned between 6.5 mL of 1 N NaOH and 25 mL of EtOAc. The NaOH solution was extracted twice more with EtOAc, and the extracts were washed with NaHCO3 and brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0-4% MeOH (0.5% NH4OH) in CH2Cl2) to provide 464 mg of 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(O)C>[CH2:32]([N:39]([C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]2[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][CH:51]=2)[CH2:42][CH2:41]1)[CH2:18][C@H:17]([OH:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:11]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(O)cc3)CC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 1.52 g (3.38 mmol) of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene and of 1 g (3.55 mmol) of trans-4-[4-(benzylamino)cyclohexyl]phenol in the base form is heated at reflux in 20 ml of absolute ethanol for 16 h. The mixture is cooled, 20 ml of a saturated ethanolic hydrochloric acid solution are added thereto and the mixture is heated at 50° C. for 1 h. The solvent is evaporated and the residue is taken up in a mixture of 100 ml of a saturated sodium bicarbonate solution and 100 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a heptane/ethyl acetate (55/45) mixture. The title compound is obtained in the form of a white solid (1.8 g, 84%). [M+H+]=631.5
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:41])([F:40])[CH2:4][CH2:5][C@H:6]([N:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:61](O)=[O:62])[CH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:45].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:9]([O:8][CH2:7][C@@H:6]([N:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:29])[CH3:30])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:5][CH2:4][C:3]([F:41])([F:40])[CH2:2][NH:1][C:61](=[O:62])[C@H:47]([CH:48]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[NH:46][C:44]([O:43][CH3:42])=[O:45])([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11]
Reactant: CCCCCN([C@@H](CCC(F)(F)CN)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN([C@@H](CCC(F)(F)CNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the material from Step 10 (42 mg, 0.066 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (39 mg, 0.132 mmol), and N,N-diisopropylethylamine (46 μL, 0.264 mmol) in 1 mL of DMF was added BOP (58 mg, 0.132 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NaHCO3, and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes (0 to 100%) to afford the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:5][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[C:7]([I:9])[CH:6]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(I)cc(I)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(I)cc(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125 %

Procedure:
To the solution of 3,5-diiodoaniline (5.0 g, 0.01 mol) in anhydrous acetone (150 mL) was added benzoylisothiocyanate (2.81 g, 0.012 mol) and the reaction mixture was stirred at room temperature for 30 min. Acetone was distilled off and the crude residue was washed with hexane to obtain desired compound as a yellow solid (6.35 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[H-].[Na+].[CH3:23][N:24]1[C:28](S(C)(=O)=O)=[N:27][N:26]=[C:25]1[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][C:28]3[N:24]([CH3:23])[C:25]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:26][N:27]=3)[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1nnc(-c2ccncc2)n1C)c1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (63.4 mg, 0.28 mmol), DMF and sodium hydride (60% dispersion in oil, 15.1 mg, 0.38 mmol) were mixed under inert atm. and stirred at r.t for 1 h, followed by addition of 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (45 mg, 0.19 mmol). After stirring at 80° C. for 24 h, the mixture was cooled to r.t., diluted with EA, sequentially washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated, in-vacuo. The crude residue was purified via column chromatagraphy using 5% MeOH in EA to isolate the title compound (11.7 mg). 1H-NMR: 8.81 (bs, 2H), 7.77 (s, 1H), 7.67 (m, 3H), 7.42 (m, 2H), 6.73 (s, 1H), 6.36 (q, 1H), 3.62 (s, 3H), 1.94 (d, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].Cl.P(Cl)(Cl)Cl>CCOCC.O1CCCC1.C1C=CC=CC=1.[Zn].O>[F:16][C:6]1[CH:5]=[C:4]([C:1]([CH3:2])=[CH:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)c1ccc(-c2ccccc2)c(F)c1

Procedure:
42.8 gm (0.20 mol) of 4-acetyl-2-fluoro-biphenyl were added in small portions, while stirring, to a Reformatsky reagent prepared from 57.5 gm (0.88 mol) of zinc and 73.5 gm (0.44 mol) of bromoacetic acid ethyl ester in 500 ml of absolute ether/tetrahydrofuran (1:1), and the resulting mixture was refluxed for one hour. Then, 1 liter of water was added, the reaction mixture was acidified with dilute hydrochloric acid, and the organic layer was separated, extracted again with water and dried over sodium sulfate. The raw 3-(2-fluoro-4-biphenylyl)-3-hydroxy-butyric acid ethyl ester remaining after the solvent had been distilled off was refluxed in 330 ml of benzene with 45 gm (0.293 mol) of phosphorus trichloride for 10 minutes, whereupon the solvent was distilled off, water was added to the residue and the precipitated oil was taken up in ether. The ether solution was washed with water and an aqueous 5% sodium bicarbonate solution until neutral, dried, filtered through charcoal, and the solvent was distilled out of the filtrate. The residue, raw 3-(2-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester (39.9 gm, 70% of theory), was used as a starting compound without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(NC(C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 21.2 %

Procedure:
The process of Example 50 was repeated except that 715 mg (2.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-D,L-aspartic acid and 215 mg of L-phenylalanine methyl ester hydrochloride, 200 mg of Prolisin and 200 mg of the inhibitor were reacted. As a result, an 110 mg amount (yield of 21.2%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D22 = -12.8 (C-1.0 dimethylformamide) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:13]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1O
Product: COC(=O)c1ccc(OC)c(O)c1
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-4-methoxybenzoic acid (Aldrich, 10 g, 59.5 mmol), methanol (250 ml) and concentrated sulfic acid (1 ml) was stirred overnight and the product was poured into a mixture of sodium bicarbonate and ice. The aqueous mixture was then extracted three times with ethyl acetate. The resulting organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Rotary evaporation of the solution gave 9.5 g of the desired product as a colorless oil. NMR (δ):3.89 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>CO.C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([N:26]([CH3:27])[CH3:25])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)ccc2[N+](=O)[O-])CC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.3 %

Procedure:
To a stirring solution of 6 g (0.016 mol) of 4-(6-chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in MeOH/CH2Cl2 (84 mL/15 mL) was added 2.2 g (0.05 mol) of dimethylamine in THF (25 mL). The reaction mixture was stirred at room temperature for 16 h, and was then concentrated. The crude product was then dissolved in CH2Cl2 (400 mL) and washed with saturated NaHCO3 (2×200 mL). The washes were combined and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 6.1 g (99%) of the desired product as a bright yellow solid. MS (electrospray): exact mass calculated for C17H27N5O4, 365.21; m/z found, 388.19 [M+Na]+. 1H NMR (400 MHz, CDCl3): 8.74 (d, J=7.07 Hz, 1H), 8.18 (d, J=9.4 Hz, 1H), 5.97 (d, J=7.3 Hz, 1H), 4.28-4.16 (m, 1H), 4.07-3.93 (m, 2H), 3.17 (s, 6H), 3.01 (t, J=11.9 Hz, 2H), 2.05 (dd, J=12.4 Hz and 3.03 Hz, 2H), 1.60-1.50 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[C:4]([CH3:14])[C:3]=1[F:15].C(=O)([O-])[O-].[K+].[K+]>CC(O)=O.C(OCC)(=O)C.CO.ClCCl.[Zn]>[C:8]([C:5]1[CH:6]=[N:7][CH:2]=[C:3]([F:15])[C:4]=1[CH3:14])#[CH:9]
Reactant: Cc1c(C#C[Si](C)(C)C)cnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: C#Cc1cncc(F)c1C
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(6-chloro-5-fluoro-4-methyl-3-pyridyl)ethynyl-trimethyl-silane (2300 mg, 9.5 mmol) in AcOH (12 mL) was added zinc (1200 mg, 19 mmol). The mixture was heated at 70° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), filtered over Celite, evaporated in vacuo and then re-dissolved in ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was dissolved in MeOH (15 mL) and treated with potassium carbonate (270 mg, 1.9 mmol). The reaction mixture was stirred for 15 minutes at room temperature and then diluted with dichloromethane (50 mL), filtered over Celite, and concentrated in vacuo to provide a residue that was purified by flash chromatography (40 g, Silica, 0-50% diethyl ether in pentane). Desired fractions were combined and evaporated in vacuo to afford the title compound as colorless, crystalline solid (1005 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.33 (s, 1H), 3.42 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+]>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]([OH:13])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 87 %

Procedure:
A solution of 0.10 mole (1 eq.) of α,α-dimethylphenylacetic acid methyl ester 2 in 150 mL of MeOH and 50 mL of water was added 1.02 mole (10.1 eq.) of KOH pellets. After stirring at room temperature for 3.5 days, the methanol was stripped off by rotary evaporation. To the residual liquid was added 100 mL of water and enough concentrated HCl to bring to ˜pH 3. The aqueous solution was extracted with Et2O (3×100 mL). The combined organic layers were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to give a white solid as α,α-dimethylphenylacetic acid 3 (87–89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K23) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (422 mg, 90%).
Reaction SMILES: [OH:1][CH:2]([CH3:15])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].CCN(CC)CC.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH:2]([CH3:15])[CH2:3][C:4](=[O:5])[CH:6]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]2[CH3:14])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1=CCCC(C)(C)C1C(=O)CC(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.6 %

Procedure:
To a solution of 3-hydroxy-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-1-butanone (1.00 g, 92% pure, 4.38 mmol), DMAP (100 mg), and NEt3 (1.0 ml, 7.2 mmol) in CH2Cl2 (20 ml) was added, at 0° C., tosylchloride (2.02 g, 10.56 mmol). The reaction medium was stirred at room temperature for 4 days. Then, the mixture was acidified with concentrated HCl and extracted twice with ether and washed with water, saturated aqueous NaHCO3 and then with saturated aqueous NaCl. Finally, the organic phases were dried over Na2SO4, concentrated at 50-60°/0.03 mbar). 0.76 g of product were thus obtained (yield: 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:6][CH:7]=1.[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[CH2:27].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:31]1[CH:32]=[CH:33][C:28](/[CH:26]=[CH:27]/[C:2]2[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]3[CH:11]=[C:12]([NH:16][C:17]4[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:14][CH:15]=3)[CH:5]=[N:6][CH:7]=2)=[CH:29][CH:30]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(Br)c2)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Reaction time: 4 h
Yield: 40.8 %

Procedure:
A mixture of 2-[3-[(E)-2-(5-bromopyridin-3-yl)vinyl]phenylamino]-3-nitropyridine (800 mg), 4-vinylpyridine (233 mg), palladium(II) acetate (27 mg), tetra-n-butylammonium chloride (616 mg) and sodium bicarbonate (432 mg) in N,N-dimethylformamide (4 ml) was stirred at 120pbC. for 4 hours. The mixture was poured into sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine (346 mg).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]([F:20])([F:19])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11].[B]1OC2C(=CC=CC=2)O1.Cl>O1CCBN1.C(OCC)(=O)C.ClCCl>[F:20][C:9]([F:8])([F:19])[C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: B1CCON1
Agent: Cl
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O[C@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2 g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time for the major product was 6.757 min. Ret. time for the minor isomer was 8.274 min.).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:11]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccccc1N
Product: O=C1NC(c2ccccc2)Nc2ccccc21

Procedure:
Anthranilamide was transformed by Method G (using benzaldehyde). M.p. 221–222° C.