Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(N(CC)C(C)C)(C)C.CN([C:31]([O:35]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:50]([O:54][C:55](=[O:58])[NH:56][NH2:57])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[CH2:12][C:31]([NH:57][NH:56][C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:58])=[O:35])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1c(N2CCC[C@H]2C(=O)O)ccc(C#N)c1Cl
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCCC2CC(=O)NNC(=O)OC(C)(C)C)ccc(C#N)c1Cl
Reaction time: 3 h

Procedure:
To a solution of 1-(3-chloro-4-cyano-2-methylphenyl)proline (0.623 g, 2.350 mmol), N,N-diisopropylethylamine (1.420 g, 11.750 mmol) and TBTU (1.113 g, 3.530 mmol) in DMF add a solution of t-butlycarbazate (0.462 g, 3.530 mmols) in DMF. Leave to stand for 3 h, then partition between ethyl acetate and 10% (w/w) aqueous citric acid. Extract the organic with 2N aqueous sodium hydroxide solution, then brine. Dry over magnesium sulphate, filter, and concentrate under reduced pressure to obtain the title compound. (0.89 g, 100%) mass spectrum (m/e): 379 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 1H), 7.42 (d, 1H), 6.38 (d, 1H), 6.22 (bs, 1H) 4.33 (t, 1H), 3.88 (m, 1H), 3.04 (m, 1H), 2.81 (m, 3H), 2.53 (m, 1H), 1.85-2.38 (m. 3H), 1.41 (s, 9H).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2.[CH3:17][O:18]C(Cl)Cl.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([CH:17]=[O:18])=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH3:16])[CH2:11]2
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1CCN(C)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1CCN(C)C2
Temperature: 0 °C
Yield: 74.5 %

Procedure:
Into a flask equipped with a mechanical stirrer, an equilibrium addition funnel, and a condenser fitted with a calcium chloride drying tube, were placed methylene chloride (150 ml) and 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (15.0 g, 0.085 mole). The solution was cooled to 0° C and stirred. Titanium tetrachloride (51.6 g, 0.272 mole) was added gradually, followed by the rapid dropwise addition of α,α-dichloromethyl methyl ether (9.8 g, 0.085 mole). After the reaction mixture was allowed to warm to room temperature, it was refluxed for 7 hours. The titanium chloride complex of the product was decomposed with water and ice, and the resulting solution kept cool as it was made basic with excess sodium hydroxide (20%). The resulting suspension was extracted with chloroform. The extract was dried over sodium sulfate and the solvent removed, affording the crude product which was vacuum distilled (b.p. 122° C/0.1 mm) to yield 13.0 g (74%) of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde. The hydrochloride salt melted at 244°-245° C after recrystallization from absolute ethanol. Anal. Calcd. for C12H13NO2Cl; C, 59.6; H, 6.7; N, 5.8; Cl, 14.7. Found: C, 59.8; H, 6.8; N, 5.8; Cl, 14.4.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.CS(CCO)(=O)=[O:24].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CS(=O)(=O)CCO
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1=Cc2c(ccc(Cl)c2O)OC1C(F)(F)F

Procedure:
To the mixture of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (2g, 6.2 mmol) and 2-methylsulfonylethanol (2.3 g, 18.5 mmol) in 40 mL of dry DMF at 0° C. was added sodium hydride (60% mineral oil suspesion, 1.48 g, 37.2 mmol) slowly with stirring. Bubbling was observed during the process. Then the resulting black solution was stirred at room temperature for three hrs. LC-MS indicated that no any more starting material was observed. The reaction was poured into ice/aqueous ammonium chloride mixture. The product was extracted with ethyl acetate, and the resulting organic solution was washed with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:1 EtOAc/hexane+1% HOAc. The product was obtained as colorless oil, 0.8 g. Part of the product was further purified on reverse phase HPLC and gave an off-white solid. LC-MS (ES+) 295.2(M+1, 100). 1H NMR (CD3OD/300 MHz) 8.11(s, 1H), 7.30(d, J=8.7 Hz, 1H), 6.53(d, J=9.0 Hz, 1 H), 5.75(q, J=7.5 Hz, 1 H),. 19F NMR(CDCl3/300 MHz) −80.31 (d, J=7.1 Hz). High resolution MS (ES−): m/e calc. For C15H6ClF3O4: 292.9828(M−H), found: 292.9853.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[NH2:29]>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:29][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 95 %

Procedure:
The title compound (61 mg, 95%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid and (S)-3,4-dichlorophenylalanine methyl ester hydrochloride as in Example 1, Part C. 1H NMR (400 MHz, CDCl3): 11.43 (br s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.90 (t, J=1.0, 1H), 7.73 (dd, J=8.8, 7.0, 1H), 7.35 (d, J=8.2, 1H), 7.14 (d, J=2.0, 1H), 7.11 (d, J=1.0, 2H), 6.89 (dd, J=8.2, 2.1, 1H), 6.48 (br d, J=7.1, 1H), 5.00-4.92 (m, 1H), 3.82 (s, 3H), 3.22 (dd, J=14.0, 5.8, 1H), 3.16 (dd, J=14.0, 5.1, 1H).
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CC=CC=1N)C=C2.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:69]=[CH:68][C:67]3[C:62](=[CH:63][CH:64]=[C:65]([O:70]C)[CH:66]=3)[CH:61]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[F:37][C:38]1[CH:39]=[C:40]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:61]=[C:62]3[C:67](=[CH:68][CH:69]=2)[CH:66]=[C:65]([OH:70])[CH:64]=[CH:63]3)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COc1ccc2cc(-c3ccccc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Agent: COc1ccc2cc(-c3ccccc3N)ccc2c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc2cc(-c3ccccc3Nc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Yield: 92.2 %

Procedure:
Synthesized from 2-(6-methoxynaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][2-(6-methoxynaphthalen-2-yl)phenyl]amine (408 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (365 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:42][CH2:43][Cl:44])(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(OCC)C>[Cl-:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCOCC
Product: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)C(C)(C)C)C=N1)c1ccc(F)cc1F
Product: [Cl-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 30.4 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (0.25 g) and chloromethyl pivalate (3.0 g) was stirred for 24 hours at 100° C. After having been cooled, the mixture was diluted with diethyl ether(5 ml), and the resulting powder was collected by filtration. The powder was purified by octadecyl silica (hereinafter briefly referred to as ODS) column chromatography (eluent: methanol/water=3/2) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,2-dimethylpropanoyloxy)methyl]-1H-1,2,4-triazolium chloride (Compound 1, 0.10 g) as a white powder.
Reaction SMILES: B(Cl)(Cl)[Cl:2].[Cl:5][C:6]1([F:14])[CH2:12][CH2:11][CH:10]2[C:8]([F:13])(O2)[CH2:7]1.[OH2:15]>ClCCl>[Cl:5][C:6]1([F:14])[CH2:12][CH2:11][CH2:10][C:8]([Cl:2])([F:13])[CH:7]1[OH:15]
Reactant: ClB(Cl)Cl
Reactant: O
Reactant: FC1(Cl)CCC2OC2(F)C1
Solvent: ClCCl
Product: OC1C(F)(Cl)CCCC1(F)Cl
Yield: 60 %

Procedure:
0.36 cm3 (0.55 eq.) of BCl3 in molar solution in dichloromethane were added at 4° C. under argon atmosphere to 0.11 g (0.65 mmol) of epoxide 2f in solution in 3 cm3 of dichloromethane. The reaction mixture was allowed to return to room temperature (1 h), 3 cm3 of distilled water were then added and the mixture was extracted with dichloromethane (4×10 cm3). The extract was dried over MgSO4, filtered and evaporated down. The crude product was purified by flash chromatography on silica (eluent ether/petroleum ether=5/95). 0.08 g of alcohol 1h were obtained having a 60% yield (macrobore GC purity>95%).
Reaction SMILES: CCCCCCCCCCCC(OCCOC[CH:19]([O:35][CH2:36][CH2:37]OC)[CH:20]1[O:24]CC(OCCOC)[CH:21]1OCCOC)=O.C1OC1>CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C.C(C(C)=O)C>[CH2:19]1[O:35][CH:36]1[CH3:37].[CH2:19]([OH:35])[CH:20]([OH:24])[CH3:21]
Reactant: CCCCCCCCCCCC(=O)OCCOCC(OCCOC)C1OCC(OCCOC)C1OCCOC
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Solvent: C1CO1
Solvent: CCC(C)=O
Product: CC(O)CO
Product: CC1CO1

Procedure:
In an alternative embodiment, the antioxidant tetrakis(methylene-3-3',5'-di-t-butyl-4'-hydroxy phenyl)propionate methane available from Ciba Geigy Corporation under the trade designation "IRGANOX 1010" antioxidant is dissolved in an amount of about 5 to about 20 weight percent of the emulsion in the organic solvent methyl ethyl ketone. The amount of methyl ethyl ketone used is in the range of around a 1 to 1 ratio with the antioxidant. The emulsifer blend is combined with this mixture by any of the aforementioned manners of addition. The emulsifier blend comprises the emulsifier polyoxyethylene (4) sorbitan monolaurate (Tween 21 available from ICI Americas, Inc.) wherein the amount of the monolaurate emulsifier is in the range of about 1 to about 5 weight percent. Another emulsifier that is used is a condensate of ethylene oxide with hydrophilic bases formed by condensing propylene oxide and propylene glycol which is available from BASF Wyandotte under the trade designation "Pluronic F-85" having an HLB of 24 and used in an amount of about 1 to about 5 weight percent. Another emulsifier that is used is the polyethoxylated vegetable oil available from GAF Corporation under the trade designation "EMULPHOR EL-719" having an HLB of 13.6 and used in an amount of about 1 to about 5 weight percent. In addition to the antioxidant, the methyl ethyl ketone, and the emulsifiers, an amount of polyalkylene polyol lubricant available under the trade designation "Pluracol V-10" available from BASF Wyandotte Corporation is added to the emulsion in an amount of about 1 to about 5 weight percent. This lubricant is added to give the emulsion additional stability. This lubricant can also be added to the sizing composition rather than to the emulsion. The polyalkylene glycol "Pluracol V-10" is a viscous, high molecular weight, liquid with a specific gravity at 25/25° C. by BWC Test of 1.089 with a flash point by ASTM D92-52 of 510° F. To the mixture of the antioxidant, methyl ethyl ketone, monolaurate, oxide glycol condensate and vegetable oil emulsifiers and polyol lubricant there is added the requisite water to produce an oil-in-water emulsion as for the preferred antioxidant discussed above.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[C:47](O)(=[O:67])[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56]/[CH:57]=[CH:58]\[CH2:59]/[CH:60]=[CH:61]\[CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH3:66]>>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:47](=[O:67])[CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56]/[CH:57]=[CH:58]\[CH2:59]/[CH:60]=[CH:61]\[CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH3:66])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCCCO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCCCCCOC(=O)CCCC/C=C\C/C=C\C/C=C\CCCCC

Procedure:
As for Example 2, Part 2 but replacing 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane with 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane and z-octadeca-9-enoic acid with z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoic acid. Chromatography yielded 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)pentane as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([P:8](C(F)(F)C(F)(F)F)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[OH-:23].[Na+:24]>COCCOC.O>[P:8]([O:23][Na:24])([C:9]([C:10]([F:13])([F:12])[F:11])([F:15])[F:14])[C:2]([C:3]([F:6])([F:5])[F:4])([F:7])[F:1]
Reactant: [OH-]
Reactant: [Na+]
Reactant: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)C(F)(F)P(O[Na])C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (3.0 mmol) of tris(pentafluoroethyl)phosphine, (C2F5)3PH, in 1,2-dimethoxyethane is treated with an excess (6 mmol) of a 1.5 M solution of NaOH in water. The mixture is stirred at room temperature for 30 min, and the solvent is subsequently removed in vacuo, giving a colourless residue, sodium bis(pentafluoroethyl)phosphinite, (C2F5)2PONa.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:28]1([N:23]2[C:22](=[O:34])[C:21]([NH:20][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]4[CH2:16][CH2:15][C:10]5([CH2:14][O:13][CH2:12][CH2:11]5)[CH2:9][CH:8]=4)[O:5][N:4]=3)=[O:19])=[C:25]([CH3:26])[N:24]2[CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1=CCC2(CCOC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC2(CCOC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [4-methyl-5-(2-oxaspiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylic acid] (40 mg, 0.152 mmol) in DMF (3 mL) was treated with 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (38.2 mg, 0.182 mmol), DIPEA (0.106 mL, 0.608 mmol) and HATU (75 mg, 0.198 mmol). The resulting mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the aqueous was extracted with EtOAc (×2). The combined organic extracts were washed with 0.5M lithium chloride (aq), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-5% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24])[C:5](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:6].[NH:26]([CH2:28][CH2:29][C:30]#[N:31])[NH2:27].[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([BH3-])#N.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24])[C:5]([NH:27][N:26]([CH2:28][CH2:29][C:30]#[N:31])[CH2:44][C:43]1[CH:46]=[CH:47][C:40]([O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:41][CH:42]=1)=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCCNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)NN(CCC#N)Cc2ccc(OCc3ccccc3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
A solution of pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (0.100 g, 0.263 mmol) in methanol (5.0 mL) was treated with 3-hydrazinopropanenitrile (0.023 mL, 0.289 mmol) and heated to reflux for 1 h. Following cooling, 4-(benzyloxy)benzaldehyde (0.067 g, 0.315 mmol), sodium cyanoborohydride (0.020 g, 0.315 mmol), and p-toluenesulfonic acid monohydrate (0.060 g, 0.315 mmol) were added and the solution stirred 30 min. at ambient temperature. Additional 4-(benzyloxy)benzaldehyde (0.067 g, 0.315 mmol), sodium cyanoborohydride (0.040 g, 0.637 mmol), and p-toluenesulfonic acid monohydrate (0.100 g, 0.526 mmol) were added and the solution stirred overnight at ambient temperature. The reaction was quenched with 6N aqueous NaOH, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (30-80% EtOAc/hexanes) gave the title compound as a white solid (0.077 g; 61%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=2.3 Hz, 1H) 7.45 (dd, J=8.8, 2.2 Hz, 2H) 7.42 (s, 1H) 7.36-7.41 (m, 2H) 7.32 (tt, J=7.0, 1.8 Hz, 1H) 7.28 (s, 1H) 7.17 (br. s., 1H) 6.94 (d, J=8.6 Hz, 2H) 6.88 (d, J=8.6 Hz, 1H) 5.05 (s, 2H) 4.61 (qq, J=6.0 Hz, 1H) 4.22 (s, 2H) 3.39 (t, J=6.6 Hz, 2H) 2.60 (t, J=6.6 Hz, 2H) 1.39 (d, J=6.1 Hz, 6H). MS (ES+) m/e 478 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[C:4]([O:21][CH3:22])[CH:3]=1.C1COCC1.C(=O)([O-])O.[Na+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(OCC)(=O)C.O>[CH2:37]([O:36][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]2)=[C:4]([O:21][CH3:22])[CH:3]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1cc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (Preparation Example 413) (4.25 g) and THF (100 mL), sodium hydrogen carbonate (1.28 g) and water (30 mL) were added, followed by dropwise addition of benzyl chloroformate (1.98 mL) under ice cooling and stirring overnight. After addition of water and extraction with ethyl acetate, the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to give tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (4.92 g) as a colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid (2.6 g) and 4-nitrophenol (1.42 g) in 35 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.91 g). The mixture was stirred at room temperature for 18 hours, and after the usual work up. the ester was crystallized from ether to give 3.65 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester 51°-56° C. Recrystallization of a portion from ether afforded the analytical specimen, mp 54°-56° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 50 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (88 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ10.5 (brs, 1H), 9.00 (brs, 1H), 8.61 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.88 (brs, 1H), 7.76 (s, 1H), 7.57 (d, J=12 Hz, 1H), 6.00 (s, 1H), 3.58 (s, 3H), 2.89 (d, J=5 Hz, 3H), 1.21 (s, 9H); MS (ESI) m/z: 500.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=1[F:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g) and 2,4-difluoroaniline (2.02 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.6 g), as pale yellow prisms (recrystallized from dichloromethane--n-hexane), m.p. 156°-157.5° C.