Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8](=[O:18])[CH:9]([CH3:17])[C:10](=O)[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-:25][Si](C)(C)C)(C)C.C(OCC)(=O)C(OCC)=O>CCOCC>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[O:18][N:25]=[C:10]([C:11]([OH:13])=[O:12])[C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1cccc(Cl)c1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(=O)C(=O)OCC
Product: Cc1c(C(=O)O)noc1-c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6 %

Procedure:
Ethyl 4-(3-chloro-2-fluorophenyl)-3-methyl-2,4-dioxobutanoate: To the solution of LiHMDS (1 M in THF) (3.19 mL, 3.19 mmol) in ether (12 mL) at −78° C. was added dropwise a solution of Intermediate 47B (0.59 g, 3.16 mmol) in ether (2 mL). After 45 min., diethyl oxalate (0.492 mL, 3.60 mmol) was added in one portion, and the reaction was warmed to rt. After 18 h, the reaction mixture was filtered, washing with ether. The filtrate was diluted with EtOAc, washed with 1 N HCl, brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography yielded the desired product (0.057 g, 6%) as a yellow oil. MS(ESI) m/z: 241.0 (M-OEt)+. 1H NMR (500 MHz, CDCl3) δ 7.80 (ddd, J=8.0, 6.3, 1.7 Hz, 1H), 7.65 (ddd, J=7.8, 7.0, 1.9 Hz, 1H), 7.23 (td, J=8.0, 0.8 Hz, 1H), 4.91 (q, J=7.2 Hz, 1H), 4.31 (qd, J=7.2, 0.8 Hz, 2H), 1.46 (dd, J=7.2, 0.8 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]([O:14][C:15](=[O:23])[N:16]([CH2:20][CH2:21]Br)[CH2:17][CH2:18]Br)[CH3:13].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:10]=[C:9]1[C:11]2([CH2:21][CH2:20][N:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:17][CH2:18]2)[CH2:1][CH2:2][C:3]2[C:8]1=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)N(CCBr)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a stirred solution of α-tetralone (289 mg, 1.98 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (600 mg, 1.98 mmol) in DMF (2 mL) at 50° C. was added NaH (119 mg, 4.95 mmol) by small portions. After being stirred at 50° C. for 12 h, the reaction was cooled to 25° C. The reaction mixture was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated. The crude product was purified via flash chromatography (gradient of 85:15 to 60:40 heptane/ethyl acetate over 20 min) to give the title compound (85 mg, 0.296 mmol) as a white solid. MS calculated for C17H22NO3 288.4. found (ESI) m/z 288.7 (M+H)+, retention time 1.58 min.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40](O)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1.[NH:43]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]1.OP=O>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:40]([N:43]3[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44]3)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][C:28]3=[O:39])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: O[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: O=PO
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CC[C@H](O)C2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
EDCI (102 mg, 0.53 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 2 ([α]D20°-102°, described as a starting material in Example 7.0a), (S)-pyrrolidin-3-ol (0.043 mL, 0.53 mmol) and HOPO (47.1 mg, 0.42 mmol) dissolved in DCM (2 mL) in a screwcap vial. The resulting solution was stirred at RT for 5 min then 50° C. for 30 min. More EDCI (˜50 mg) was added to complete the reaction. The solution was washed with a 10% aq. citric acid solution, water, brine and dried over magnesium sulfate. The solvent was evaporated and the crude product purified by flash chromatography on silica gel (40 g) eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-((S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (95%) as a off-white foam. Mass Spectrum: M+H+ 500. NMR Spectrum (CDCl3): 1.60 (d, 3H), 1.89-2.11 (m, 1H), 2.54 (bs, 0.5H), 2.81 (bs, 0.5H), 3.29-3.43 (m, 2H), 3.51 (bs, 4H), 3.64-3.78 (m, 2H), 3.79-3.91 (m, 5H), 4.42 (bs, 0.5H), 4.54 (bs, 0.5H), 4.59 (bs, 0.5H), 4.70 (bs, 0.5H), 4.87-4.95 (m, 1H), 5.54 (bs, 1H), 5.89-6.01 (m, 2H), 6.09 (dd, 1H), 7.85 (s, 0.5H), 7.87 (s, 0.5H), 8.18 (bs, 0.5H), 8.25 (bs, 0.5H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][C:67]([C:70]#[N:71])=[N:68][CH:69]=1>>[C:70]([C:67]1[N:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][N:66]=1)#[N:71]
Reactant: N#Cc1ncc(N)cn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2cnc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.37 g, 2.9 mmol), diphenylphosphinic chloride (0.27 g, 1.1 mmol), then reacted with 5-aminopyrimidine-2-carbonitrile (Accelachem) (0.1 g, 0.9 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-cyano-pyrimidin-5-yl)-amide as a yellow solid (Yield 30 mg, 9%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]CC)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:13]([C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[N:16]=1)[CH3:14]>C(O)C.CCN(CC)CC>[CH2:13]([C:15]1[N:20]=[C:19]([N:5]2[CH2:4][CH2:3][C:2]([CH3:1])([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)[CH:18]=[CH:17][N:16]=1)[CH3:14]
Reactant: CCc1nc(Cl)cc(Cl)n1
Reactant: CCOC(=O)C1(C)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1nccc(N2CCC(C)(C(=O)O)CC2)n1
Reaction time: 20 h

Procedure:
1-(2-Ethylpyrimidin-4yl)-4-methyl-piperidine-4-carboxylic acid was prepared on a 3 mmol 4-methyl-4-ethoxycarbonyl-piperidine (as TFA salt) in 7 ml ethanol and 1 ml Et3N treated with a solution of 0.531 g 2-ethyl-4,6-dichloropyrimidine in 4 ml ethanol. After 20 hours at ambient temp. The ethanol was removed and the residue partitioned between water and ethanol, washed with sodium hydrogen carbonate solution and brine. Evaporated to give gum (88.3%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][CH3:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]([CH3:12])[S:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CNC1CCC2(CC1)OCCO2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCC2(CC1)OCCO2)S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methyl-amine (1.5 g, 9 mmol), CH2Cl2 (50 mL), and Et3N (1.7 mL, 12 mmol) was stirred with 4-fluorobenzene sulfonyl chloride (1.7 g, 9 mmol) at room temperature. After 1 hour, the reaction mixture was concentrated and the residue purified by flash chromatography on silica gel to afford 2.1 g of N-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-fluoro-N-methyl-benzenesulfonamide. Mass spectrometric data [M+H]+=330.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([C:17]([CH3:28])([CH3:27])[CH2:18][C:19](N2CCOCC2)=[O:20])[CH:16]=1>C1COCC1>[CH:1]1([C:19](=[O:20])[CH2:18][C:17]([C:15]2[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=2[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: BrC1CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C1CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of cyclopropyl bromide (0.120 g) in THF (0.8 mL) cooled to −70° C., a solution of tert-butyl lithium (1.7 M in pentane, 0.8 mL) was added dropwise over 5 minutes. The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.29 g) in THF (1 mL) was then added all at once and the mixture was stirred for 30 minutes. The mixture was quenched with EtOH (0.3 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated to give the title compound as an oil (0.23 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+:29]=[N-:30])[O:24][CH2:23]2)[CH:17]([CH:32]([O:34][C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[CH3:33])[C:16]3=[O:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Reactant: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Using anhydrous conditions, 1.25 g of product from Example 45 in 27 ml of anhydrous tetrahydrofuran, is cooled to -78° C. under argon. 0.325 ml of isobutyl chloroformate is added, followed by 2.7 ml of lithium bis(trimethylsilyl)amide. The reaction mixture is stirred at -78° C. for 1 hour, followed by stirring at -55° C. for another hour and then concentrated in vacuo. The residue is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 1.22 g of the desired product.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
A solution of (2-fluoro-3-methylphenyl)-(4-methoxy-phenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) in pyridine was heated at 100 C for 24-48 hrs. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:4]2[C:5]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[S:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3sc(-c4ccc(F)cc4)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N2CC[C@@H](N)C2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound of example 338 (66 mg, 0.15 mmol) in dichloromethane (6 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and co-evaporated with toluene. The residue was directly used for further reaction without any purification.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14].[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21](F)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([O:14][CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=3)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1
Reactant: Cn1cc(Br)c2ccc(F)nc21
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
Potassium tert-butoxide (137.4 g; 1.19 mol) and DMF (1.44 L) are charged into a flask, and a solution of 2-pyridylmethanol (145.8 g, 1.34 mol) in DMF (306 mL) is added over 15 min. The flask is cooled as necessary to maintain room temperature. The mixture is stirred at room temperature for 40 minutes. A solution of 3-bromo-6-fluoro-1-methyl-pyrrolo[2,3-b]pyridine (170 g, 742.2 mmol) in DMF (306 mL) is added over 15 min., maintaining the temperature between 20 and 25° C. The mixture is stirred for 2 h. Water (1.7 L) is added slowly to the mixture, cooling as necessary, followed by extraction with EtOAc (4×1.0 L). The combined extracts are washed with water (4×1.0 L), then brine, and dried over sodium sulphate, filtered and concentrated to leave the product as a yellow solid (235.1 g, 0.74 moles). MS (m/z): 318.0/320.0.
Reaction SMILES: [N:1]1([C:7]([O:9][C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH2:28])[O:19][C@@H:18]2[CH3:30])=[O:15])[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=C.C1(=O)C=CC(=O)C=C1>C(Cl)CCl>[N:1]1([C:7]([O:9][C@@H:10]([CH3:11])/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH:28]/[C@H:33]3[O:40][C:39]([CH3:41])([CH3:42])[CH2:38][C@:35]4([O:37][CH2:36]4)[C@@H:34]3[OH:43])[O:19][C@@H:18]2[CH3:30])=[O:15])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Reactant: C=C[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCCl
Product: CC(/C=C/[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Temperature: 42 °C
Reaction time: 14 h

Procedure:
To a stirred solution of recovered (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (22.1 mg) in ClCH2CH2Cl (200 μL) was added benzoquinone (1.0 mg, 0.010 mmol) and Grela Catalyst (2.0 mg, 3.0 μmol) at 23° C. under an open atmosphere. The reaction mixture was then heated to 42° C. After an additional 14 h at the same temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10→80% EtOAc in hexanes) on silica gel (8 mL) to give (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide as a pale tan solid. The combined yield of (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide after one cycle is 15.7 mg (44%). Some of the tan (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide was purified by semi-preparative HPLC (Conditions: flow rate=2.5 mL, from 30% to 100% MeCN in H2O over 30 min; Column=Varian Pursuit XRs C18 column (5 μm packing, 250×10 mm); Retention time 16.70 min; Detection=237 nm) to afford (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide as a colorless oil that was subsequently used for biological experiments.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (11.6 g, 0.05 mol), DMSO (20 ml) and phenethylamine (12.1 g, 0.1 mol) is heated at 80° C. overnight. The reaction mixture is poured into water (1 L), and the precipitate that forms is collected by filtration and washed with water. The solid is dissolved in hot ethyl acetate, and then the solution is dried over MgSO4, filtered and evaporated to a small volume. Hexane is added, and then the mixture is cooled in an ice bath, and then the product that crystallizes is collected by filtration, washed with hexane and dried to afford 12.5 g of 1-ethyl-N-(phenylethyl)-1H-pyrazolo[3,4-b]quinoline-4 amine, m.p. 157°-158° C.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]2[CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=[C:22]2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(CCO)c[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(CCO)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Triphenylmethyl chloride (24.5 g, 88 mmol) in DMF (100 ml) was added dropwise over 1 hr to a solution of 2-methyl-4-(2-hydroxyethyl)imidazole (10 g, 80 mmol) and triethylamine in DMF (100 ml). The reaction mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The resultant solid was triturated with water (3×500 ml) and ether (200 ml), collected by filtration and dried under vacuum at 60° C. to give the title compound (23.7 g, 80%) as a pale yellow solid. NMR 1.43 (d, 3H), 1.62 (s, 3H), 2.53 (s, 1H), 4.80 (q, 1H), 6.59 (s, 1H), 7.13 (m, 6H), 7.37 (m, 9H); m/z 369.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)([O-])=O.[Sn](Cl)Cl>C(Cl)(Cl)Cl.Cl>[NH2:15][C:18]1[CH:19]=[C:20]([S:24]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 50 g (0.463 mole) of p-cresol (4-methylphenol) and 37 mL (0.458 mole) of pyridine dissolved in 250 mL of chloroform was added 50 g (0.226 mole) of 3-nitrobenzenesulfonyl chloride. The reaction was allowed to stir at ambient temperature. After 2 hours, the reaction was judged complete by TLC and the volatiles were removed by rotary evaporation. The resulting residue was treated with 400 mL of 0.5 M sodium bicarbonate. The insoluble product was collected and washed with sodium bicarbonate (2 times, 200 mL each) and water (2 times, 300 mL each). The solid was then treated with methanol (200 mL) followed by water (200 mL). The solid was collected by vacuum filtration and washed with water. This solid was treated with 170 g (0.897 mole) of tin (II) chloride dissolved in 250 mL of concentrated HCl. The reaction was allowed to stir at ambient temperature for 40 hours. TLC indicated that the reaction was incomplete, so the reaction was heated at 50 C. for 27 hours. The solid precipitate was collected by vacuum filtration and was washed with 6N HCl. The solid was extracted with ethyl acetate and, water. The ethyl acetate layer was washed with brine, dried with magnesium sulfate, filtered, and the volatiles removed by rotary evaporation to yield 42.5 g of compound as an oil that solidified on standing.