Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][CH:75]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:73][CH2:74][CH:75]([N:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)[CH2:76][CH2:77]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 75 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-benzaldehyde were reacted to produce the title compound (75%). 1H NMR (d-6 DMSO): 12.50 (br s, 1H), 9.85 (br s, 1H), 8.09 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.83 (br s, 1H), 7.29 (s, 1H), 6.77 (d, J=9 Hz, 1H), 6.66 (s, 1H), 6.38 (s, 2H), 5.15 (m, 1H), 3.95-4.30 (m, 7H), 3.69 (t, J=10 Hz, 2H), 3.48 (m, 3H), 3.13 (m, 2H), 2.82-2.96 (m, 4H), 2.63 (d, J=8 Hz, 1H), 2.11-2.26 (m, 3H), 2.08 (s, 1H), 1.69 (m, 2H), 1.41 (d, J=9 Hz, 1H). MS: 579.20 (M+H). HPLC retention time: 1.91 minutes (G Method).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([OH:9])[C:7]=1[F:8]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([OH:9])[C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/c1cc(O)c(F)c(F)c1
Solvent: CCO
Product: CCOC(=O)CCc1cc(O)c(F)c(F)c1
Reaction time: 21 h
Yield: 94.6 %

Procedure:
A 2 L Parr hydrogenation flask was charged with ethyl (2E)-3-(3,4-difluoro-5-hydroxyphenyl)-2-propenoate (91.1 g) and 750 mL of absolute ethanol. The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this was added 10.15 g of catalyst (5% Pd/C—wet) and placed under hydrogen atmosphere (55 psi). After 21 h of stirring, starting material was still present so the reaction was filtered, washed with methanol and DCM and concentrated. The residue was diluted with 550 mL of absolute ethanol and deoxygenated by bubbling nitrogen for 30 minutes. An additional 9.32 g of 10% Pd/C (dry) was added and the reaction placed under hydrogen atmosphere (60 psi) for another 22 h. The reaction was still not complete. The reaction was then filtered as above and the residue was dissolved in 450 mL of ethanol and an additional 10 g of 10% Pd/C (dry) was added and the reaction placed under hydrogen atmosphere (60 psi) for another 20 h. The reaction was then filtered though a pad of Celite and washed with CH3OH and CH2Cl2 and concentrated to get the desired product (86.9 g) in 95% yield.
Reaction SMILES: C(N1C2=CC3C(=CC2=C(C2SC(Br)=CC=2)C1=O)N(CCCCCC)C(=O)C=3C1SC(Br)=CC=1)CCCCC.CC1(C)C(C)(C)OB(C(CCCC)C[C:49]2[C:61]3[C:60](CC)(CC)[C:59]4[C:54](=[CH:55][CH:56]=[C:57](B5OC(C)(C)C(C)(C)O5)[CH:58]=4)[C:53]=3[CH:52]=[CH:51][CH:50]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].BrC1SC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C1(C)C=CC=CC=1.O>[CH:49]1[C:61]2[CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1
Reactant: CCCCC(Cc1cccc2c1C(CC)(CC)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1-2)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: Brc1cccs1
Agent: CCCCCCN1C(=O)C(c2ccc(Br)s2)=c2cc3c(cc21)=C(c1ccc(Br)s1)C(=O)N3CCCCCC
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 372 %

Procedure:
A mixture of 1,5-Dihexyl-3,7-di-(5-bromothiophen-2-yl)-1H,5H-pyrrolo[2,3-f]indole-2,6-dione (0.150 g, 0.221 mmol), 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,9-di-ethylhexylfluorene (0.149 g, 0232 mmol), Pd2(dba)3 (5.0 mg), (o-tol)3P (3.0 mg), K3PO4 (0.187 g) and toluene/H2O (20 mL/1 mL) was heated at reflux for 24 h. 2-bromothiophene (0.035 g, 0.22 mmol) in toluene (1 mL) was added and the resulting mixture was stirred for another 12 h. Then, after cooling to room temperature, the mixture was dropped into methanol to precipitate. After being filtered and dried, the precipitation was Soxhlet extracted with methanol, acetone, hexane, dichloromethane and chloroform in succession. The chloroform solution was concentrated and reprecipitated in methanol. The solid was filtered and dried to yield polymer (0.165 g, 82.5%) as a blue-green solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[C:18]2[C:13]=1[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]2[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Br)cn2)c2c(F)ccc(F)c2c1=O
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3cn[nH]c3)cn2)c2c(F)ccc(F)c2c1=O
Temperature: 100 °C

Procedure:
To a solution of ethyl 1-[(5-bromopyridin-2-yl)methyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (3.00 g, 7.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (5.42 g, 18.4 mmol), and 1 N cesium carbonate (14.2 mL, 14.2 mmol) in 50 mL of THF under nitrogen was added bis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reaction mixture was heated to 100° C. for 20 hours, then cooled to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, and the resultant brown solid was collected to provide ethyl 5,8-difluoro-4-oxo-1-{[5-(1H-pyrazol-4-yl)pyridin-2-yl]methyl}-1,4-dihydroquinoline-3-carboxylate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 411.0 for M+H+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14]C)=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:17].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:17]
Reactant: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 8-chloro-7-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7c, 600 mg, 2.43 mmol) was dissolved in THF (10 ml) and MeOH (5 ml). 1N NaOH (5 ml) was added and the solution stirred at RT overnight. The solution was acidified with 4N HCl then extracted into DCM and the aqueous washed ×3 with DCM. The organic portions were evaporated to give the title compound which was used without further purification (426 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.79 (m, 4H) 2.83 (t, J=6.06 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 13.75 (br. s., 1H) [M+H] calc'd for C10H9ClFNO3, 246. found, 246.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22]([O:31][CH2:32]Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:32][O:31][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:19]
Reactant: CCCCCCCC(=O)OCCl
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: CCCCCCCC(=O)OCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 26.4 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 300 mg) and chloromethyl octanoate (483 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-6, 95 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc(Cl)cc1
Yield: 97.4 %

Procedure:
A mixture of 200 g of 4-chlorophenyl acetic acid, 178.5 g of thionyl chloride and 600 ml of benzene was heated at reflux for 6 hours and then concentrated in vacuo. The residue was vacuum distilled, giving 215.8 g of 4-chlorophenyl acetyl chloride, bp 94°-95° C. (2.5 mmHg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[CH:14][C:13]([CH:23]=[O:24])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25]B(O)O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:25])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:12]=[C:13]([CH:23]=[O:24])[CH:14]=1
Reactant: CB(O)O
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2F)cn1
Temperature: 80 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
Under an argon atmosphere, a mixture of 1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (365 mg), methylboronic acid (90 mg), tetrakis(triphenylphosphine)palladium (116 mg), potassium carbonate (691 mg) and 1,4-dioxane (25 mL) was stirred at 80° C. for 3 days. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as a yellow solid (yield 134 mg, 39%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH:15]([C:19]1[S:20][CH:21]=[C:22]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]2[C:32](=O)[C:31](=[O:34])[C:30]=2[O:35]C)[N:23]=1)[C:16]([NH2:18])=[NH:17]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:32]2[C:31](=[O:34])[C:30](=[O:35])[C:29]=2[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:22]2[N:23]=[C:19]([NH:15][C:16]([NH2:18])=[NH:17])[S:20][CH:21]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NCCCCc2csc(NC(=N)N)n2)c(=O)c1=O
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Solvent: CO
Product: N=C(N)Nc1nc(CCCCNc2c(NCCCCc3csc(NC(=N)N)n3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)thiazole (0.105 g) and 1-[4-(2-guanidinothiazol-4-yl)butylamino]-2-methoxycyclobutene-3,4-dione (0.16 g) in dry methanol (5 ml) was stirred for 18 hours at room temperature. The white solid was filtered off, washed with methanol and dried in vacuo to give 1,2-bis[4-(2-guanidinothiazol-4-yl)butylamino]cyclobutene-3,4-dione, 0.16 g., m.p. 228°-229° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].C(O)(=O)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:7]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([CH:16]4[CH2:18][CH2:17]4)=[O:15])[CH2:10][C:9]=3[S:19][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:29])[N:1]=1
Reactant: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1N=C(c2ccccc2Cl)c2c(sc3c2CCN(C(=O)C2CC2)C3)NC1=O
Yield: 23.9 %

Procedure:
12.95 g of 2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 260 ml of toluene and 90 ml of pyridine, to which 5.4 g of acetic acid was added, followed by heating under reflux for 5 hours. After removal of the solvent by distillation, benzene was added and the resultant crystals were collected by filtration to obtain 2.96 g of the intended compound. The mother liquor was subjected to silica gel column chromatography (elution solvent: ethyl acetate:hexane=4:6) to obtain 3.84 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:14]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1ccsc1N
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Amino-thiophene-3-carboxylic acid amide (8.73 g, 61.4 mmole) was dissolved in pyridine (100 ml) cooled to 0° C. and 2-fluorobenzoyl chloride was added dropwise over 20 min, then reaction was allowed to warm to room temperature with stirring overnight. The pyridine was removed under vacuum, added dichloromethane and water. Product precipitated as a grey solid and was washed with dilute hydrochloric acid, water and air dried. The dichloromethane layer was separated, washed with dilute hydrochloric acid, and water, dried over sodium sulfate (anh.) and solvent removed to give a total of 12.45 g product (77% yield).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:6]=1[CH:14](O)[CH2:15][CH3:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:14]([C:6]1[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:5]=1[OH:4])[CH2:15][CH3:16]
Reactant: CCCc1ccc(C(O)CC)c(OCOC)c1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1ccc(CCC)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a solution of 1-[2-(methoxymethoxy)-4-propylphenyl]propan-1-ol (12.7 g, 53.3 mmol) and triethylsilane (21.3 mL, 133 mmol) in CH2Cl2 (120 mL) at 0° C. was added trifluoroacetic acid (16.4 mL, 213 mmol) slowly with an outlet needle attached to the round-bottom flask. The solution was stirred at 0° C. for 5 min and then at room temperature for 14 h. Water (40 mL) was added and the mixture was stirred at room temperature for 2 h. Extraction in CH2Cl2 (2×150 mL) with 50% saturated brine (5×100 mL) removed all of the trifluoroacetic acid. Flash chromatography with silica gel (gradient to 5% EtOAc/hexanes) furnished the title compound as a light green liquid (3.60 g, 38% yield): 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H, J=7.3 Hz), 0.97 (t, 3H, J=7.3 Hz), 1.62 (m, 4H), 2.52 (m, 4H), 4.58 (s, 1H), 6.60 (s, 1H), 6.69 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=7.6 Hz); MS m/e 179 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)[CH:9]=1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42](B(O)O)[CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:42]3[CH:41]=[N:40][C:49]4[C:44]([CH:43]=3)=[CH:45][CH:46]=[CH:47][CH:48]=4)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)[CH:9]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate (703 mol), quinolin-3-ylboronic acid (350 mg, 2.00 mmol), Pd(dppf)Cl2—CH2Cl2 (82 mg, 0.10 mmol) and potassium phosphate (636 mg, 3.0 mmol) in a mixture of dioxane/H2O (9:1, 20 mL) was heated at 100° C. for 5 h under argon. The reaction mixture was cooled down and diluted with EtOAC, washed with Brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Biotage (CH2Cl2/EtOAc, 10:1 to 3:1) to give the title compound as brown solid. LC/MS RT=2.49 min. Mass calculated for, M+H 690.37, observed 389.17.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH2:10])[CH2:5]1)[CH:2]=[CH2:3].C(O[CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: C=CCN1CCCC(N)C1
Solvent: Cc1ccccc1
Product: C=CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 1-allyl-3-aminopiperidine and 9-acetoxyxanthene in dry toluene for 24 hours and working up by the procedure of Example 1 gives N-(N-allyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCl.ClC1(CC=NO)C=CC=CC1.[CH3:24][C:25]([CH3:28])([O-:27])[CH3:26].[K+].Cl>C(Cl)(Cl)Cl.C(O)(C)(C)C>[C:25]([O:27][C:8](=[N:9][OH:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:28])([CH3:26])[CH3:24]
Reactant: ON=CCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: ClCl
Agent: ON=CCC1(Cl)C=CC=CC1
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(Cc1ccccc1)=NO

Procedure:
Using the procedure of Example I, phenyl acetaldehyde oxime in chloroform is reacted with chlorine gas introduced at -5° to 0° C. To the resulting solution of 1-chlorophenyl acetaldehyde oxime is added dropwise with stirring a solution of potassium t-butoxide in t-butanol. The reaction is allowed to go to completion and any residual potassium t-butoxide is neutralized with hydrogen chloride gas. The precipitated potassium chloride is removed by filtration, and the filtrate concentrated under reduced pressure to provide the desired 1-(t-butoxy)-2-phenyl acetaldehyde oxime.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[O:12]C(C)(C)C)[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH3:5][C:6]1([CH3:28])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[O:4][CH2:3][CH2:2][F:1])[C@H:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: OCCF
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Example 48, 2-fluoro-ethanol and the product of Step A were reacted to obtain benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+53° (c=0.5% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[I:10]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[I:10][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:4]=1[NH2:5]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(Cl)c1I
Yield: 45.7 %

Procedure:
Dissolve 3,5-dichloroaniline (10 g, 61.5 mmol) in 1:1 acetic acid/methylene chloride (200 mL). Add N-iodosuccinimide (16.9 g, 61.5 mmol) as a solid and stir at room temperature in the absence of light for 8 hours. Pour the solution into saturated sodium hydrogen carbonate (200 mL) and extract into methylene chloride (100 mL). Wash with saturated sodium hydrogen carbonate (200 mL), dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound (8.1 g, 45%); mp 61°-63° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=O)[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[OH:31][NH2:32].C(N(CC)CC)C.[Cl-].[NH4+]>C(O)C>[OH:31][N:32]=[C:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=NO)CC1C(=O)O3
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
Compound 1 (172 mg, 0.429 mmol) obtained in Example 1 was dissolved in ethanol (4.0 mL), and hydroxyamine hydrochloride (89.5 mg, 1.29 mmol) and triethylamine (178 μL, 1.29 mmol) were added thereto at room temperature, followed by stirring for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain the title compound (160 mg, 90%) as a mixture of E-form and Z-form.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:4]([OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC=CC=CC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC=CCCC=CCCCCCCO
Temperature: 0 °C
Yield: 41 %

Procedure:
The ethylhexadecadienoate was reduced with lithium aluminum hydride (LAH) in tetrahydrofuran as follows. An oven dried 3-neck flask equipped with a magnetic stirrer, reflux condenser and an addition funnel was charged with 2 equivalents of LAH in dry tetrahydrofuran (THF). The reaction vessel and contents were maintained under a positive flow of nitrogen as 1 equivalent of ester (ethylhexadecadienoate) dissolved in an equal volume of dry THF was added dropwise to the stirred LAH suspension at a rate to maintain the THF at a gentle boil. After ester addition was complete, the reaction mixture was refluxed gently for an additional 2 hours, cooled to 0° C. and one equivalent of water slowly added to decompose excess LAH, followed by addition of 15% aqueous NaOH. The resulting gray gel was filtered and the organic layer washed with water, dried over adsorbent and concentrated on a rotary evaporator. Yields of about 41% of the desired 7,11-hexadecadien-1-ol were obtained.