Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.CC1ON=C(C2C=CN=CN=2)C=1C(O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1conc1-c1ccc(F)cn1
Agent: Cc1onc(-c2ccncn2)c1C(=O)O
Product: OCc1conc1-c1ccc(F)cn1
Yield: 70 %

Procedure:
As described for example 114g, 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid (562 mg, 2.7 mmol) was converted, instead of 5-methyl-3-pyrimidin-4-yl-isoxazole-4-carboxylic acid, to the title compound (367 mg, 70%) which was obtained as an off white solid. MS: m/e=195.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=2)[C:14]2=[N:25][NH:26][C:27](=[O:28])[N:13]2[CH:12]=1)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>ClCCl>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=2)[C:14]2=[N:25][NH:26][C:27](=[O:28])[N:13]2[CH:12]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl[(2E)-3-(3-oxo-2,3-dihydrobenzo[g][1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (7-7) (3.0 mg, 0.0077 mmol) in a ¼ mixture of dichloromethane and TFA (1.0 ml) was stirred at room temperature for 15 min and concentrated to dryness to give the deprotected material 7-8 as a TFA salt. LRMS m/z: found 291.1, calcd. (M+H) 291.1. 1H NMR (500 MHz, CD3OD) δ: 3.88 (d, J=6.6 Hz, 2H), 6.35 (dt, J=6.6, 15.6 Hz, 1H), 7.31 (d, J=15.7 Hz, 1H), 7.63 (s, 1H), 7.65-7.68 (m, 2H), 8.05-8.11 (m, 2H), 8.38 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:24].CN(C)C=O>C(OCC)(=O)C>[CH2:36]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][NH:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:34][CH2:35]1)[CH3:37]
Reactant: O=C1Nc2cccnc2N(C(=O)NCCBr)c2ccccc21
Reactant: CCN(CC)CCCCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 60 %

Procedure:
Prepared analogously to Example 109 from 11-[[[2-bromo-ethyl]amino]carbonyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]-piperidine, but using dimethylformamide instead of acetonitrile, in a yield of 60% of theory. Colourless crystals, m.p. 167° C. (ethyl acetate).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)[CH:8]=[CH2:9])(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[C].[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][CH3:9])[CH:10]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(OC(C)=O)cc(OC(C)=O)c1
Yield: 76.9 %

Procedure:
3,5-Diacetoxystyrene (580 mg) is dissolved in a mixture of ethyl acetate (6 ml) and ethanol (2 ml), and the mixture is subjected to catalytic reduction with using 10% palladium-carbon (51.4% aqueous, 50 mg) under atmospheric pressure. Two hours thereafter, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 1,3-diacetoxy-5-ethylbenzene (450 mg).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:21]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1CNc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 81.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 170 mg of 3-methylindoline and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 310 μl of pyridine and 6.0 ml of N,N-dimethylformamide. 367 mg of 2-[2-(3-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white crystalline powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:13]([N:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=O)[CH:14]([CH3:16])[CH3:15].C[O-].[Li+]>CN(C)C=O>[CH2:13]([N:17]1[CH:21]=[N:20][N:19]=[C:18]1[C:22]1[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26](/[CH:27]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])[CH:29]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2nncn2CC(C)C)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2nncn2CC(C)C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-acetyl-benzoic acid (0.12 g, 0.75 mmol) and 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.24 g, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added lithium methoxide (1.0M in methanol, 3.0 mL, 3.0 mmol). The solution was allowed to stir overnight and additional lithium methoxide (0.11 g, 2.8 mmol). The reaction was quenched with water after 20 hours. The aqueous solution was washed ethyl acetate, acidified to pH 4. The precipitate was filtered, washed with ethanol and dried in vacuo to afford the title compound as a light yellow solid: m.p.>240° C. (dec.). 1H NMR (DMSO-d6) δ 8.59 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 8.07 (s, 1H), 8.04–8.01 (m, 3H), 7.85 (d, J=15.7 Hz, 1H), 6.84 (s, 1H), 4.06 (s, 3H), 3.92 (s, 3H), 3.66 (d, J=7.2 Hz, 2H), 1.87–1.74 (m, 1H), 0.72 (d, J=6.7 Hz, 6H). MS m/z=436 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25]C)=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:2][CH3:3].[OH-].[Na+]>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:22][C:23]([OH:25])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 1.5 g (4.3 mmol) of the compound from Example XXXIX and 10 ml (10 mmol) of 1N sodium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Cc1cc(C)cc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(C)cc(C)c1
Yield: 25.8 %

Procedure:
Prepared according to the procedure described for Example 98 using 3-amino-4-methoxy-N-phenyl-benzamide (0.974 g, 4.01 mmol) and 3,5-dimethylphenyl isothiocyanate (0.66 g, 4.04 mmol) to afford the product (0.42 g); m.p. 203-205° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of n-butyllithium (2.0 M in hexanes, 3.45 mL, 7.5 mmol) (Aldrich) in tetrahydrofuran (3 mL) at −78° C. was added a solution of 3-bromo-pyridine (0.96 g, 8.1 mmol) (Aldrich) in tetrahydrofuran (6 mL) dropwisely. After the addition, the resulting dark solution was stirred for additional 15 minutes. A solution of 6-chloroisatin (0.5 g, 2.76 mmol) (Crescent) in tetrahydrofuran (5 mL) was added dropwisely and the crude was warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was quenched with water. The mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-6-Chloro-3-hydroxy-3-pyridin-3-yl-1,3-dihydro-indol-2-one as a yellow solid. (Yield 0.27 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.O>ClCCl>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:31]([NH:14][C:10]2[CH2:11][O:12][CH2:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)([CH3:15])[N:9]=2)([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC1(c2cccc(Br)c2)COCC(N)=N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(NC2=NC(C)(c3cccc(Br)c3)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (3.7 g, 13.8 mmol) and triethylamine (1.5 g, 1.1 eq) in dichloromethane (20 ml) was cooled to 0° C. and 4,4′-dimethoxytriphenylmethyl chloride (5.12 g, 1.1 eq) was added. The reaction mixture was stirred at room temperature overnight. Thereafter, water was added to the mixture and the organic phase was separated, dried over sodium sulfate and concentrated at reduced pressure. The crude was purified by chromatography on silica gel to yield the (RS)-[bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine as a yellow oil (7.0 g, 99% of theory). Mass (calculated) C3H31BrN2O3 [571.52]; (found) [M+H]+=571.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:85])[C:81]([F:84])([F:83])[F:82])[C:69](OCC#N)=[O:70])=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(#N)C>[C:60]([O:64][C:65]([NH:67][C@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:85])[C:81]([F:83])([F:84])[F:82])[C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])=[O:66])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)C(F)(F)F)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 4.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (81 mg, 0.127 mmol) and (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk53) (194 mg, 0.509 mmol) in acetonitrile (0.7 mL) was added to buffer A (20 mL), and the mixture was stirred at room temperature for 1.75 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk54) (5.3 mg, 4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:34])[C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([N+:29]([O-])=O)[C:22]=1[O:32][CH3:33]>C(O)C.[Pd]>[NH2:29][C:23]1[C:22]([O:32][CH3:33])=[C:21]([C:26]([O:27][CH3:28])=[CH:25][CH:24]=1)[C:20]([NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[CH3:18])=[O:34]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(OC)c1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 16 h

Procedure:
A solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2,6-dimethoxy-3-nitrobenzamide (200 mg, 0.4 mmol) (see Example I3) in ethanol (8 ml) charged with Pd/C 10% (64 mg, 0.06 mmol) was stirred under a hydrogen atmosphere for 16 hours. After filtration the mixture was concentrated. The residue was used without further purification.
Reaction SMILES: N1C2C(=CC=CC=2)CC1=O.C(C1OC=C([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])C=1)=O.N1CCCCC1>CCO>[C:21]([OH:23])(=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(-c2coc(C=O)c2)c1
Agent: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)c1ccccc1
Yield: 184.6 %

Procedure:
A solution of oxindole (400 mg, 2.4 mmol), methyl 3-(5-formylfuran-3-yl)benzoate (518 mg, 2.4 mmol) and piperidine (0.24 mL, 2.4 mmol) in EtOH (10 mL) was stirred at rt 30 min. The resulting precipitate was collected by filtration to yield desired (E)-3-(5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (541 mg). LCMS (ES): m/z 366 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:6](=[O:7])[CH:5]=[CH:4]1.CC1(C)O[C@@H]([C@@H](O)[C@H](O)[C@@H]2OC(C)(C)OC2)CO1.N1C=CN=C1.[C:32]([Si:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[Si:36]([O:1][CH2:2][C@H:3]1[O:8][C:6](=[O:7])[CH:5]=[CH:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C[C@@H](CO)O1
Agent: CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (S)-5-hydroxy-2-penten-4-olide [3.2 g, 28.07 mmol; prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol (Aldrich) in a 3-step sequence described by Hafele and Jager in Liebigs Ann. Chem. 1987, 85-87], in dry DMF (50 ml), at 0° C., was added imidazole (2.95 g, 42.1 mmol), followed by tert-butylchlorodiphenylsilane (7.95 ml, 30.9 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for a period of 1 h. Then, the solvent was evaporated and the residue was purified on a silica gel column using hexane/EtOAc (7:3 v/v) as the eluent. The appropriate fractions were evaporated and gave 9.0 g (91%) of MSC-006. 13C-NMR (CDCl3)δ: 19.40, 26.88, 63.53, 83.40, 122.89, 128.05, 130.20, 132.68, 132.95, 135.71, 135.76, 154.20. (The carbonyl carbon was not detected).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:25]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:20]=[C:21]([Cl:24])[C:22]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([C:25]2([C:30]([F:33])([F:32])[F:31])[CH2:29][CH2:28][N:27]([C:2]3[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=3)[CH2:26]2)[CH:20]=[C:21]([Cl:24])[C:22]=1[Cl:23]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 100 °C
Yield: 86.5 %

Procedure:
Ethyl 2-chloro-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (1.4 g) [see J. Het. Chem., 22, 1621 (1985)], 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidine (1.7 g), and potassium carbonate (0.8 g) were added to N,N-dimethylformamide (50 mL), followed by heating at 100° C. for five hours. After cooling, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (2.5 g, 86%).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH2:5]([CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C=O.C(O)(=O)C>C(#N)C>[CH3:1][N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(CCC2CCCN2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCCC1CCc1ccccc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium cyanoborohydride (17.4 mg, 0.27 mmol) was added portion-wise to a stirred solution of 2-phenethyl pyrrolidine (30 mg, 0.17 mmol) and 37% aqueous formaldehyde (0.07 mL, 0.87 mmol) in 1.5 mL acetonitrile at 25° C. The mixture was stirred for 15 min, acetic acid was added dropwise until the reaction was neutral, and the mixture was stirred for an additional 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10 mL diethyl ether and the ethereal solution was washed with 10 mL of saturated Na2CO3 and extracted twice with 5 mL of 1N HCl. The combined HCl solutions were then basicified with saturated Na2CO3 to obtain a pH=10 and extracted three times with 10 mL dichloromethane. The combined dichloromethane layers were washed with 10 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on thin layer chromatography to give 1-methyl-2-phenethyl pyrrolidine free base; 18 mg, 55% yield.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([OH:17])[CH:7]=1>N1C=CC=CC=1>[CH:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([O:17][S:2]([OH:5])(=[O:4])=[O:3])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(OS(=O)(=O)O)cc1
Temperature: 0 °C

Procedure:
Chlorosulfonic acid is added to the pyridine solution to form a reaction mixture. Preferably, the chlorosulfonic acid is added dropwise while maintaining the cooled temperature. About 1 mole of chlorosulfonic acid per mole of coumaric acid may be used. A slight excess is acceptable. Due to the reaction's exothermic nature, the reaction mixture is preferably stirred at the cooled temperature, e.g., about 0° C., for a time sufficient to allow the p-coumaric acid and the chlorosulfonic acid to react and form zosteric acid. Preferably, the reaction mixture is stirred for about 2 to about 4 hours at the low temperature, more preferably about 2.5 to about 3 hours.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:42])[CH2:10][CH2:11][CH2:12][C@H:13]([OH:41])/[CH:14]=[CH:15]/[C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@@H:18]([Cl:28])[C@@H:17]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH2:39][CH3:40])=[O:36])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[Cl:28][C@H:18]1[C@H:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH2:39][CH3:40])=[O:36])[C@@H:16](/[CH:15]=[CH:14]/[C@@H:13]([OH:41])[CH2:12][CH2:11][CH2:10][C@H:9]([OH:8])[CH3:42])[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19]1
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 84.3 %

Procedure:
A solution of silyl ether 14 (316 mg, 0.50 mmol) was stirred at 35° C. with 2 mL of 1.0M TBAF/THF in a vial for 9.5 h. TLC indicated starting material was mostly desilylated and the reaction was concentrated in vacuo. The residual crude products were taken up in 50 mL of ethyl acetate and washed sequentially with saturated ammonium chloride (50 mL), brine (50 mL), and dried over 10 g of anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo. The residual products were purified by flash column chromatography on 40 g of silica gel eluted in 1:1 hexanes:EtOAc, then straight EtOAc. Combination of appropriate fractions and removal of the solvents yielded 218 mg (84%) of diol 15 as an oil; 1H NMR (CDCl3): 0.94 (t, J=7.5 Hz, 31H), 1.18 (d, J=6.3 Hz, 3H), 1.31 (m, 6H), 1.42-1.90 (m, 19H), 2.10-2.50 (m, 7H), 3.48 (m, 1H), 3.72-4.16 (m, 7H), 4.64 (dt, 1H), 5.57 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:5]#N)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.[OH2:27]>CCCCCC.C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:5]=[O:27])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=C(C#N)C(C)C
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CC=C(C=O)C(C)C
Temperature: -70 °C
Yield: 90 %

Procedure:
To a solution of 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienenitril (2Z compound, 217 mg, 1 mmol) in n-hexane (4 ml) was added a 1 M solution of diisobutylaluminium hydride in toluene (2 ml) with stirring under argon atmosphere at -70° C. After two-hour-stirring at the same temperature, water (0.8 ml) was added to the mixture followed by removal of the cooling bath and vigorous stirring. The resultant while precipitates were filtered and washed with n-hexane. The filtrate was combined with a 10% aqueous solution of oxalic acid and stirred for 3 hours. The organic layer was extracted and separated, washed with water, dried over MgSO4, and concentrated. The above manipulation was conducted under argon atmosphere. The resultant residue was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=50:l) to obtain the aimed 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienal (198 mg, 90%).