Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[C:3]([O:5]CC)=[O:4].C(O)C.[OH-].[K+]>O>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)/[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)/C(C)=C/CCC#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\CCC#Cc1ccccc1)C(=O)O
Yield: 94.9 %

Procedure:
The ethyl 2-methyl-7-phenyl-(2E)-heptene-6-ynoate (1.0 g, 4.13 mmol), ethanol (4 ml), potassium hydroxide (1 g) and water (4 ml) were heated together under a nitrogen atmosphere at 50° C. for 2 hours. The reaction mixture was worked up as in Example 1 to give 0.84 g (95% of theory) of 2-methyl-7-phenyl-(2E)-hepten-6-ynoic acid as a colourless solid.
Reaction SMILES: [C@@H:1]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[C@@H:18]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]1O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>>[C@@H:18]1([N:27]2[CH:34]=[C:33]([CH3:1])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:19]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
Referring now to the drawing, FIG. 1 shows barley malt sprouts being fed to a dry mill 11, where they are ground to finer than 60 mesh, and normally 100 to 200 mesh (U.S. standard series mesh size). The ground sprouts in line 12 are admixed with an aqueous medium containing low levels of an activator (e.g., a metallic salt), and optionally, with recycled filtered liquor from line 17 to form a dispersion or mixture. Hydrolytic enzymes (e.g., pectinase, cellulase, hemicellulase, glucanase, etc.) may be added as processing aids to reduce the viscosity of the dispersion of barley malt sprouts, thereby allowing easier recovery of any thymidine in line 14. The resulting dispersion is heated and held at about 40° to 60° C. within kettle 15. The dispersion within kettle 15 is gently stirred continuously during the incubation period. The product which comprises crude liquor is then filtered in filter 16, and, as discussed above, some of the filtered liquor may be recycled or returned to feed line 12 by recycle line 17. Large molecular weight impurities are removed by filter 16 which can be either an ultrafiltration unit or a precipitator (e.g., to perform selective precipitation). The filtered liquor is sent to a solvent extraction unit or a unit containing an adsorption/desorption material on a suitable support in 18. A by-product of the solvent extraction process is removed from unit 18 by means of line 20. The resultant solvent extraction product from the filtered liquor yields thymidine and normally also contains other nucleosides, including cytidine, uridine, deoxy-guanosine and guanosine. The solvent extraction product on purified liquor is then sent via line 21 to a liquid chromatographic separator 22 to fractionate the nucleosides to obtain liquid thymidine. The liquid thymidine is then sent via line 23 to an evaporator 24 to concentrate the liquid thymidine. Evaporated liquid from the concentrated thymidine is removed from evaporator 24 via line 25. The concentrated thymidine is fed via line 26 to a crystallization unit 27. The crystalline thymidine is fed via line 28 to a dryer 29 and subsequently to packaging.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.Cl.[CH:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][NH:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>ClCCCl.CCOC(C)=O>[CH:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][N:38]2[C:17]([C@@H:16]2[CH2:20][CH2:21][CH2:22][N:15]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])=[O:19])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCc2ccccc2C1C1CCCCC1
Reaction time: 1 h
Yield: 109.2 %

Procedure:
N-methylmorpholine (0.873 mL) was added to a solution of 1-(tert-butoxycarbonyl)-L-proline (1.28 g) in 1,2-dichloroethane (10 mL) under ice-cooling, followed by further addition of pivaloyl chloride (0.734 mL). The reaction liquid was stirred for 1 hour, and N-methylmorpholine (1.09 mL) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) were then added thereto. The mixture was stirred at room temperature for 15 hours. To the reaction solution were added EtOAc and an aqueous 1 M HCl solution. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl (2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidine-1-carboxylate (1.79 g).
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([C:19]1[C:20](O)=[C:21]([CH:24]=[CH:25][CH:26]=1)C=O)([OH:18])=[O:17].S(NN)(C1C=CC(C)=CC=1)(=O)=O.CN(C)[CH:42]=[O:43]>>[C:16]([C:19]1[CH:26]=[CH:25][C:24]([CH:21]=[N:14][NH:13][C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[S:15])=[C:42]([OH:43])[CH:20]=1)([OH:18])=[O:17]
Reactant: NNC(=S)Nc1cccc2ccccc12
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(C(=O)O)c1O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Product: O=C(O)c1ccc(C=NNC(=S)Nc2cccc3ccccc23)c(O)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 4-(naphth-1-yl)-3-thiosemicarbazide (38 mg, 0.175 mmol) and 4 carboxy-2-hydroxybenzaldehyde (35 mg, 0.211 mmol) in dimethylformamide (2 mL) was shaken with 4 Å molecular sieves for 2.5 h. PS-TsNHNH2 resin (50 mg, 0.147 mmol) was added, shaking continued for 1 h, then the resin filtered off. Water was added to the filtrate and the precipitated solid was filtered, washed (water, ether) and dried to give the title compound (52 mg, 81%) as a solid. MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4)cc23)cc1

Procedure:
The title compound, light yellow solid (41 mg, 31%), MS (ISP) m/z=374.1 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Yield: 147.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-(5-bromo-7-cyano-1H-indazol-3-yl)-1-piperidine-carboxylate (Intermediate 3) (0.200 g, 0.493 mmols) and trifluoroacetic acid (0.25 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 hrs. The solution was cooled and the solvent removed in vacuo to give the crude amine (222 mg) trifluoroacetate salt, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH3:18])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH3:4].[CH2:19]([Zn]CC)C.ICI>C(Cl)Cl>[CH3:4][CH:3]1[CH2:19][CH:2]1[CH2:1][N:5]([CH2:16][CH2:17][CH3:18])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC[Zn]CC
Reactant: C/C=C/CN(CCC)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: ICI
Product: CCCN(CC1CC1C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][N:5]=1.[H][H].[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26](Cl)(=[O:28])=[O:27]>COCCOC>[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26]([NH:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][N:5]=1)(=[O:28])=[O:27]
Reactant: [H][H]
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ncc(Cl)cc3Cl)cccc12
Temperature: 75 °C
Yield: 6.6 %

Procedure:
Oil-free sodium hydride (48 mg) was added to a solution of 2-amino-3,5-dichloropyridine (326 mg) in 1,2-dimethoxyethane (20 ml). After evolution of hydrogen ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (540 mg) was added and the mixture was heated at 75° C. for 3 days. Volatile material was removed by evaporation and the residue was purified by flash chromatography. Elution with dichloromethane/hexane (3:2 v/v) and trituration of the resulting foam with ether/hexane (1:10 v/v) gave 5-(dimethylamino)-N-(3,5-dichloro-2-pyridyl)-1-naphthalenesulphonamide (52 mg), m.p. 161°-163° C.; mass spectrum [+ve FAB, dimethylsulphoxide (DMSO)/glycerol (GLY)]: 396 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:7]=[C:6]2[C:18]([NH:20][NH2:21])=[O:19].C(N(CC)CC)C.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]2[C:6]([C:18]3[O:19][C:29](=[O:30])[NH:21][N:20]=3)=[N:7][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9](=[O:11])[C:10]=12
Reactant: NNC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1scc2c(-c3n[nH]c(=O)o3)nn(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a ice cooled solution of 5-amino-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid hydrazide (2.0 g, 6.64 mmol), triethylamine (0.67 g, 6.64 mmol) in dry tetrahydrofuran (50 ml) was added 1,1′-carbonyidiimidazole (1.3 g, 8.30 mmol). The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (100 ml) was added and the precipitate was filtered off and washed with water (2×25 ml), diethyl ether (20 ml) and dried in vacuo at 50° C. for 16 h affording 1.7 g (78%) of the title compound as a solid.
Reaction SMILES: [Na][Na].[C:3]([CH2:11][C:12]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])=O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O.[NH2:25][NH2:26]>CO.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:12]1[CH:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:26][N:25]=1)([OH:18])=[O:17]
Reactant: O=C(CC(=O)c1ccccc1C(=O)O)c1ccccc1
Reactant: NN
Agent: Cl
Agent: [Na][Na]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2ccccc2)[nH]n1

Procedure:
To a slurry of 100 g of the disodium salt of 2-benzoylacetylbenzoic acid in 400 ml of methanol is added first 12.5 g concentrated hydrochloric acid, followed by 11 g of hydrazine hydrate. This reaction mixture is heated at reflux for one-half hour, cooled to 5°-10°, acidified to pH 3 with concentrated hydrochloric acid, and diluted with 300 ml of water. The crystals are filtered off and recrystallized from ethanol-water, yielding 59 g of 3-(2-carboxyphenyl)-5-phenylpyrazole, mp 204°-205.5° .
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[O:9])=[C:5]([CH3:7])[N:6]=1.NC1SC(C(NCC)=O)=C(C)N=1.[CH2:27]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][CH2:12][C:13]#[N:14])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[O:39])=[CH:41][CH:42]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(Cc2ccccc2)cc1
Reactant: Cc1nc(N)sc1C(=O)NCCC#N
Agent: CCNC(=O)c1sc(N)nc1C
Product: Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCCC#N

Procedure:
Following the procedure as described in Example 20, making variation only as required to use 2-amino-N-(2-cyanoethyl)-4-methylthiazole-5-carboxamide to replace 2-amino-N-ethyl-4-methylthiazole-5-carboxamide to react with 4-benzylbenzoyl chloride, the title compound was obtained; 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.27-7.10 (m, 5H), 4.03 (s, 2H), 3.54 (t, J=6.6 Hz, 2H), 2.73 (t, J=6.6 Hz, 2H), 2.54 (s, 3H), 2.32 (s, 1H); MS (ES+) m/z 405 (M+1).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[C:49]([NH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=1)(=[O:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:49]([NH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)=[O:27])[CH2:22]2)=[O:58])=[CH:55][CH:54]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(C(=O)N2CCN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)[C@H](C(=O)N[C@@H]3CCCc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Intermediate 7 (191 mg, 0.351 mmol) is dissolved in DMF (10 mL), to which is added DIEA (0.305 mL, 1.75 mmol). This mixture is stirred at room temperature for 0.5 h. 4-Acetamidobenzoic acid (66 mg, 0.368 mmol) is added, and stirring is continued for continued 1 h. HOBt (52 mg, 0.385 mmol) and HBTU (146 mg, 0.385 mmol) are then added and the entire mixture is stirred at room temperature for 2 h. The reaction mixture is diluted with EtOAc (100 mL) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine. The EtOAc layer is then dried with MgSO4, filtered, and the solvent removed at room temperature under reduced pressure to afford a colorless gum. This material is purified by flash chromatography on silica gel (EtOAc) to give the title compound as a white foam (211 mg, 85% yield): 1H NMR δ (CDCl3) 6.40-7.62 (m, 11H), 4.25-5.30 (m, 5H), 3.93 (“br d”, 1H, Jobs=11.9 Hz), 3.47 (“br id”, 1H, Jobs=11.4, 3 Hz), 2.65-3.30 (br m, 7H), 1.70-2.22 (br m, 8H), 1.48 and 1.46 (s, 9H total), 1.28-1.34 (m, 3H), 0.60-1.12 (br m, 7H); LCMS (APCl+) 706.7 (MH+, 100%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[C:1]1([NH:7][C:4]2[CH:5]=[CH:6][C:1]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:2][CH:3]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(NC3CCCCC3)cc2)cc1
Reaction time: 1.5 h

Procedure:
Into a three neck 500 ml flask equipped with a thermometer, stirrer, Dean Stark trap and condenser was charged 18.4 grams of N-phenylquinoneimine, 150 ml toluene, 19.9 cyclohexylamine and 5 drops methanesulfonic acid. The reaction was conducted at 110°C. for 1.5 hours after which time the product was washed with 200 ml water containing 10 grams of Na2S2O4. The product was decanted, filtered and stripped at a pot temperature of 100°C. at 4 mm Hg. 27 grams of N-phenyl-N'-cyclohexyl-p-phenylenediamine were recovered.
Reaction SMILES: C(C1[C:6](O)=[C:7]([CH:10]=[C:11](/[CH:13]=[CH:14]/[C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:12]=1)C=O)(CC)C.[CH:30](C1C(O)=C(C=C(/C=C/C(=O)C2C=CC(C)=CC=2)C=1)C=O)([CH2:32][CH3:33])[CH3:31].[C:54]([O:62][CH2:63][CH3:64])(=[O:61])[CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].N1CCCCC1>C(O)C>[CH:30]([C:64]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15](=[O:28])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:10]=[C:7]2[C:63]=1[O:62][C:54](=[O:61])[C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:6]2)([CH2:32][CH3:33])[CH3:31]
Reactant: CCC(C)c1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc(C=O)c1O
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(/C=C/C(=O)c3cc(OC)c(OC)c(OC)c3)cc(C(C)CC)c2oc1=O

Procedure:
A solution of (E)-3-sec-butyl-2-hydroxy-5-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-enyl)benzaldehyde of formula III (0.5 g, 1.26 mmol), diethyl malonate (0.20 g, 1.26 mmol) in ethanol (30 mL) was treated with piperidine (0.2 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (35 mL) was added and extracted 3-fold with 15 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-ethyl 8-sec-butyl-2-oxo-6-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-enyl)-2 H-chromene-3-carboxylate (General Formula IV). (0.49 g, 78% yield). White solid, m. p. 128-129° C.; 1H NMR (CDCl3 300 MHz): δ 8.56 (s, 1H), 7.83-7.75 (m, 3H), 7.49 (d, J=15.6 Hz, 1H), 7.31-7.29 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.95 (brs, 9H), 3.45-3.36 (m, 1H), 1.78-1.69 (m, 2H), 1.42 (t, J=7.1 Hz, 3H) 3.33 (d, J=6.9 Hz, 3H) 0.89 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 188.8, 162.9, 156.3, 153.9, 153.3, 148.6, 142.9, 142.7, 136.7, 133.2, 131.8, 131.6, 126.8, 122.7, 118.8, 118.2, 106.4, 62.1, 61.1, 56.6, 50.8, 33.6, 29.7, 20.5, 14.3, 12.1; ESI-MS (m/z): 495 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[ClH:1].[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][NH2:21]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: NN
Solvent: O
Solvent: CO
Product: Cl
Product: NCCOc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
7-Chloro-3-(2-fluorophenyl)-6-(2-phthalimidoethoxy)-1,2-benzisoxazole (8.0 g) is heated under reflux for 4 hrs in 75 ml of methanol containing 1.3 g of 85% hydrazine hydrate. The solid is filtered and the methanol is evaporated. The combined solids are distributed between water and ethyl acetate. The organic phase is dried and concentrated under reduced pressure to give 5.30 g (87%) as a glass that crystallizes slowly. The hydrochloride forms smoothly in ether with a trace of methanol as crystals, mp 235°-240°. The analytical sample is recrystallized from propanol/methanol and has mp 240°-243°.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]1[C:11]#[N:12])[CH:2]=[CH2:3].[C:13]([Si](C)(C)C)([F:16])([F:15])[F:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:4]1[CH:8]=[C:7]([CH:9]([OH:10])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:5]1[C:11]#[N:12])[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C=O)cc1C#N
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a chilled (0° C.) solution of 1-allyl-4-formyl-1H-pyrrole-2-carbonitrile (1.25 g, 7.8 mmol, 1 equiv.) in 10 mL of THF was added CF3TMS (1.5 ml, 9.5 mmol, 1.2 equiv.) dropwise followed by TBAF (1M in THF, 9.4 ml, 9.4 mmol, 1.2 equiv.) slowly dropwise. The cold bath was then removed and the mixture was stirred at room temperature. After 2 hours, the reaction was quenched with water and extracted with EtOAc. The organic was dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc-hexanes (5-40% gradient) to afford 1-allyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrrole-2-carbonitrile which was used without further purification.