Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[O:12][C:11]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: CCOP(=O)(OCC)c1ccc(-c2cccc(N)c2)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)c1ccc(-c2ccc(Br)c(N)c2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of diethyl 5-(3-aminophenyl)-2-furanphosphonate (1 mmol), NBS (0.9 mmol) and AIBN (0.1 mmol) in 30 mL of CCl4 was stirred at rt for 2 h. Extraction and chromatography provided diethyl 5-(4-bromo-3-aminophenyl)-2-furanphosphonate as an oil.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:18]([C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:23]=3)=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][C@H:13]([CH3:34])[N:14]3[C:30]([O:32][CH3:33])=[O:31])=[C:6]([C:37]#[N:38])[CH:5]=1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:18]([C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:39])[CH2:26][CH2:25]4)[CH:23]=3)=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][C@H:13]([CH3:34])[N:14]3[C:30]([O:32][CH3:33])=[O:31])=[C:6]([C:37]#[N:38])[CH:5]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Formaldehyde (37% aqueous solution, 0.015 mL, 0.198 mmol) was added to a solution of (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.010 g, 0.020 mmol) in methanol (1.0 mL), and the reaction mixture stirred for 2 h. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (8.4 mg, 0.040 mmol) was added. The reaction mixture stirred at 0° C. and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0095 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06 (br d, J=6.74 Hz, 3H), 1.47-1.69 (m, 4H), 1.71-2.13 (m, 4H), 2.19 (s, 3H), 2.71-2.90 (m, 2H), 3.72 (s, 3H), 3.93-4.13 (m, 1H), 4.32-4.45 (m, 1H), 4.50-4.65 (m, 1H), 6.35-6.54 (m, 1H), 7.45-7.65 (m, 4H), 7.65-7.72 (m, 1H), 7.97 (s, 1H), 8.11 (d, J=2.64 Hz, 1H). MS (ESI, pos. ion) m/z 521 [M+H]+.
Reaction SMILES: Cl[O-].[Na+].[Br-].[Na+].[OH-].[Na+].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH:12]=[O:13].S([O-])([O-])=[O:23].[Na+].[Na+].Cl>O.C1CCCCC1>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1)[C:12]([OH:23])=[O:13]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To an aqueous solution of sodium hypochlorite (15.3 ml, 25.7 mmol, 1.2 equiv.) and sodium bromide (2.6 g, 25.7 mmol, 1.2 equiv.) in sodium hydroxide solution (47%, 4.55 ml, 53.5 mmol, 2.50 equiv.) and water (12.5 ml) was added slowly (during 25 min) at 50° C. 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (5.0 g, 21.4 mmol). The reaction mixture was stirred at 50° C. for 60 min, cooled to ambient temperature and quenched upon addition of aqueous sodium sulfite solution (20%, 16.2 ml, 25.7 mmol, 1.2 equiv.) to give a light turbid suspension. The suspension was stirred for 15 min, treated with HCl (37%, 5.0 ml, 59.1 mmol, 2.76 equiv.) adjusting the pH to 1, whereupon a white precipitate formed. This precipitate was extracted with toluene (30 ml), the organic phase was washed with brine (30 ml), whereas the aqueous phase was washed with TBME (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under vacuum to give the crude product as light yellow solid (5.13 g, 98.8% yield). The crude product was dissolved in hot cyclohexane (25 ml), and the solution was cooled to ambient temperature, whereupon white crystals precipitated. The crystals were filtered off, washed with cyclohexane (5 ml) dried under vacuum until weight constancy to give the title compound as white crystals (3.65 g, 69.6% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:13])([F:14])[F:1])[C:8]([OH:10])=[O:9])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-trifluoromethoxybenzoic acid (2.96 g) in concentrated sulphuric acid (19 ml) at room temperature was added a mixture of concentrated nitric acid (8.5 ml) and concentrated sulphuric acid (8.5 ml) drop-wise. After 15 min a white precipitate had formed. The reaction was slowly poured onto ice (approx. 100 ml). Once the ice had melted the resulting suspension was filtered, and the residue washed with water (3×10 ml) and then dried in vacuo to give the title compound as a white solid (3.41 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)=[O:18].O>CN(C=O)C>[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:11]2[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=[CH:10]2)=[CH:25][CH:26]=1)=[O:18]
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:3) to provide the title compound as white powder (511 mg, yield 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:12]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC(C)([O-])C.[Na+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[C:12]([CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:22][CH:23]=2)=[N:26][CH:27]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: CC(=O)N1CCC(c2cccnc2Oc2ccc(N)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Into a sealed tube were added 1-(4-(2-(4-aminophenoxy)pyridin-3-yl)piperidin-1-yl)ethanone (0.11 g, 0.37 mmol), 2-chloro-5-methylpyridine (0.043 g, 0.33 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.02 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.012 g, 0.034 mmol), sodium tert-butoxide (0.097 g, 1.01 mmol), and toluene (1.6 mL). After the mixture was degassed for 5 min, the reaction was stirred at 100° C. for 16 h. The cooled reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc(10% MeOH)/Hexanes) gave a crude crop of the desired product. Further purification via reverse phase HPLC afforded 1-(4-(2-(4-(5-methylpyridin-2-ylamino)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone as a white amorphous solid. MS (ESI, pos. ion) m/z: 403.0 (M+1). IC50 (uM) 0.002844.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:3]1.[N+:15]([CH3:18])([O-:17])=[O:16].N12CCCN=C1CCCCC2>>[F:1][C:2]1([F:14])[CH2:3][CH2:4][CH:5]([CH:8]([CH2:18][N+:15]([O-:17])=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:7]1
Reactant: COC(=O)C=CC1CCC(F)(F)CC1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C[N+](=O)[O-])C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 3-(4,4-difluorocyclohexyl)prop-2-enoate (4.054 g, 0.198 mol, 1 eq) is dissolved in nitromethane (23 L, 0.423 mol, 21.3 eq) and 1,8-diazabicyclo[5,4,0]undec-7-ene (3.025 g, 0.198 mol, 1 eq) is added at room temperature. The solution is stirred overnight at room temperature then evaporated. The residue is dissolved in ethyl acetate and the solution is washed with 1 M HCl and water. The organic phase is dried with MgSO4 and evaporated under vacuum. The residue is purified by chromatography over silicagel (eluent: CH2Cl2 100%) to afford methyl 3-(4,4-difluorocyclohexyl)-4-nitrobutanoate a1-20.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:5]([CH3:28])[C:6](=[O:27])[C:7]2[C:8]([N:26]=1)=[C:9]([O:24]C)[C:10]1[C:11](=[O:23])[N:12]([CH3:22])[C:13]([CH2:19][O:20]C)=[N:14][C:15]=1[C:16]=2[O:17]C.CO.[K+].[Br-]>C1C=CC=CC=1>[OH:2][CH2:3][C:4]1[N:5]([CH3:28])[C:6](=[O:27])[C:7]2[C:8]([N:26]=1)=[C:9]([OH:24])[C:10]1[C:11](=[O:23])[N:12]([CH3:22])[C:13]([CH2:19][OH:20])=[N:14][C:15]=1[C:16]=2[OH:17]
Reactant: COCc1nc2c(OC)c3c(=O)n(C)c(COC)nc3c(OC)c2c(=O)n1C
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Product: Cn1c(CO)nc2c(O)c3c(=O)n(C)c(CO)nc3c(O)c2c1=O
Temperature: 25 °C

Procedure:
To 172 mg 10.441 mmol) of 15, suspended in 50 mL of dry benzene, was added an excess of 99% BBr, (up to 10 fold excess). The resulting mixture was refluxed for 7 hours. After cooling the reaction mixture to room temperature, methanol was added to quench the reaction. The solvent was evaporated off in vacuo and the product purified by rinsing successively with water and methanol and then dried: 106.5 mg (72%) yield; dec pt >245° C. IR (KBr pellet) 3384, 1645, 1618, 1443, 1430, 1379, 1325, 1209, 1079, 965, 793 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) 11.86 (2H, s, 5- and 10-hydroxyls), 4.62 (4H, s, methylenes), 3.61 (6H, s, 3- and 8- methyls); mass spectrum (EI model m/z 334 (P+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.N1CCOCC1.C(N1C[CH2:45][N:44]2[CH2:47][CH2:48][N:49]([CH2:50][CH2:51]CC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:49]5[CH2:48][CH2:47][N:44]([CH3:45])[CH2:51][CH2:50]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCN1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), morpholine (130 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 115 mg of 110 (yield=31%). 1H NMR (CDCl3, 400 MHz): δ8.12-8.10 (m, 1H), 7.58-7.52 (m, 1H), 7.15-7.05 (m, 4H), 6.55 (d, J=9.2 Hz, 1H), 4.25-4.23 (m, 2H), 3.75-3.63 (m, 5H), 3.12-3.10 (m, 2H), 2.93-2.91 (m, 4H), 2.62-2.57 (m, 3H). LC-MS (ESI): m/z=480 [M+H]+
Reaction SMILES: NCCCOCCOCCO.[CH2:12]1[C:26](=O)[C:25]2[C:16](=[C:17]([OH:29])[C:18]3[C:23]([C:24]=2[OH:28])=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14](=O)[CH2:13]1.C1C=CC2C(=O)C3C(=C(O)C=CC=3O)C(=O)C=2C=1>O>[CH:19]1[C:18]2[C:17](=[O:29])[C:16]3[C:25](=[CH:26][CH:12]=[CH:13][CH:14]=3)[C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)c2c1c(O)c1ccccc1c2O
Agent: NCCCOCCOCCO
Agent: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 70 °C

Procedure:
To a 1 L glass reaction vessel equipped with a mechanical stirrer, temperature probe, water-cooled condenser, and a gas inlet tube was added 2-[2-(3-aminopropoxy)ethoxy]ethanol (291 g), leucoquinizarin (52 g), and quinizarin (152 g). The reaction mixture was heated under a nitrogen atmosphere to 70° C., at which time agitation was started. The reaction mixture was then heated to 80° C. After heating at that temperature for 4 hours, a gentle stream of air was introduced into the reaction mixture and heating at 80° C. was continued with the air sparge in order to oxidize the reaction mixture. After heating an additional 5 hours, the oxidation was complete. The reaction mixture was then cooled to room temperature to produce a blue anthraquinone colorant having a maximum absorbance at 639 nanometers and a color value of 31.5 (absorbance/g/L in methanol). The colorant contained 0.2% 1-(3-(2-(2-hydroxyethoxy)ethoxy)propylamino-4-hydroxyanthraquinone (i.e. violet impurity) and 0.7% of water and methanol insoluble black impurity. The structure of the anthraquinone colorant is shown below:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH:32]=O)[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].ClCCCl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([OH:9])=[O:8])[CH:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: O=C(O)C1CCCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCCCC4C(=O)O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.9 %

Procedure:
Piperidine-2-carboxylic acid (0.125 g, 0.967 mmol) as HCl salt was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol) in 1,2-dichloroethane (5 mL, 60 mmol) and acetic acid (0.500 mL, 8.79 mmol). The mixture was heated to reflux while stirring overnight. Reaction cooled to room temperature and then sodium triacetoxyborohydride (546 mg, 2.58 mmol) was added in small portions. The reaction was then left stirring overnight. Reaction was then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 3 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-2-carboxylic acid as a yellow solid (0.8%). ESI-LCMS (424 M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.34-12.58 (m, 1H), 11.20-11.53 (m, 1H), 8.01 (s, 1H), 7.68-7.93 (m, 3H), 7.41 (s, 1H), 7.02-7.22 (m, 1H), 4.35 (br. s., 3H), 3.23-3.43 (m, 2H), 2.86-3.09 (m, 2H), 1.74-2.30 (m, 8H), 1.00-1.52 (m, 5H), 0.87 (s, 9H)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:9]3[N:10]([N:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=3)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)(=[O:24])C>>[CH3:15][O:14][C:11]1[N:10]2[N:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=[C:9]2[C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:24])[NH:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)c2cc(C(C)C)nn12
Reactant: CC(=O)O
Product: COc1ccc(-c2ccc(=O)[nH]n2)c2cc(C(C)C)nn12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The compound of Example 268 (50 mg) was dissolved in acetic acid (2 mL) and the solution was stirred at 90° C. for 3 hours. Subsequently, the solvent was concentrated and the residue was purified by silica gel column chromatography (methanol:ethyl acetate 1:9) to afford the title compound as a pale yellow powder (26 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(CCCCCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCCCc1cccc(OCc2ccccc2)c1

Procedure:
7-Bromo-1-(3-benzyloxy-phenyl)-heptane (10.2) was prepared as in 10.1 using 9.2 (0.4 g, 1.48 mmol), K2CO3 (0.612 g, 4.44 mmol) and benzyl bromide (0.278 g, 1.63 mmol). The title, compound (10.2) was isolated as a viscous liquid after purification by flash column chromatography (0.411 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][S:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(N)Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-3-phenyl-propionic acid methyl ester is dissolved in 25 mL of methylene chloride and the reaction charged with triethylamine (0.97 mL, 7 mmol) and 4-chlorobenzenesulfonylchloride at 0° C. The reaction is allowed to warm to room temperature (rt) and stirred overnight. The reaction is quenched with sodium bicarbonate, extracted with methylene chloride, dried over sodium sulfate, and concentrated in vacuo. The resultant solid is triturated with 20% ethylacetate/hexanes to provide the title compound. 13C NMR (100 MHz, CDCl3) 39.5, 52.8, 57.1, 127.5, 128.8, 128.9, 129.5, 129.6, 135.1, 138.4, 139.4, 171.5. MS 354.1 m/z (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:46][C:47]([F:50])([F:49])[F:48])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[C:24]([N:29]4[C:33](=[O:34])[CH2:32][C@H:31]([NH:35]C(=O)OCC5C=CC=CC=5)[CH2:30]4)=[N:25][N:26]([CH3:28])[CH:27]=3)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[C].[Pd].CO>[NH2:35][C@@H:31]1[CH2:30][N:29]([C:24]2[C:23]([NH:22][C:20]([C:18]3[N:19]=[C:15]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([N:8]([CH2:46][C:47]([F:49])([F:48])[F:50])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:14]=4)[O:16][CH:17]=3)=[O:21])=[CH:27][N:26]([CH3:28])[N:25]=2)[C:33](=[O:34])[CH2:32]1
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](NC(=O)OCc3ccccc3)CC2=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a mixture of benzyl ((3S)-1-(4-(((2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazol-4-yl)carbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidin-3-yl)carbamate (1.0 g), THF (7.2 mL) and methanol (7.2 mL) was added 10% palladium-carbon (154 mg), and the mixture was stirred at room temperature for 1.5 hr under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (817 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-:3])=[O:2].[CH3:17][NH:18][CH3:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:17][N:18]([CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CNC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 4-nitro-2-(trifluoromethyl)benzoic acid (10 g, 42.5 mmol), dimethylamine (hydrochloride, 4.51 g, 55.3 mmol) and Et3N (17.78 mL, 128 mmol) in DCM (150 mL) stirred under nitrogen at 20° C. was added HATU (19.41 g, 51.0 mmol) in one charge. The reaction mixture was stirred at 20° C. for 2 h. Then the solution was distributed between DCM and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting N,N-dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10 g, 25.2 mmol, 59.2% yield) was used in the next step without further purification. TLC (PE/EA=5:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=1.8 Hz, 1H), 8.46 (dd, J=2.0, 8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 2.79 (s, 6H); ES-LCMS m/z 263.0 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCC=CCO)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl erucate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 35.5 gms (0.1 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[S:12]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCSC(=S)Nc1ccccn1
Product: CC(C)(C)OC(=O)NCCCCNC(=S)Nc1ccccn1
Yield: 340.3 %

Procedure:
Ethyl 2-pyridyldithiocarbamate (500 mg) and t-butyl 4-aminobutylcarbamate (474 mg) were reacted in a similar manner to in Reference Example 58, and crystallized from n-hexane-diethyl ether to give the title compound (2.78 g).