Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:50][C:51]([CH3:53])=[O:52]>>[OH:52][C:51]([CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16])([CH3:53])[CH3:50]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(N2C(=O)C(C(C)(C)O)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Yield: 19 %

Procedure:
To (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.40 g, 0.64 mmol) in acetone (30 mL) was added saturated aqueous sodium bicarbonate (3 mL). The reaction was heated to reflux for 12 hours, cooled, and concentrated. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried and concentrated. Purification by flash column chromatography using 100-40% A/B, where A=1:1 dichloromethane/hexanes and B=3:1 ethyl acetate/acetone, as eluent provided the title compound as a white solid (0.095 g, 19%).
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>ClCCl>[Si:17]([O:4][CH2:3][CH2:2][S:1][CH2:5][CH2:6][OH:7])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCSCCO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCSCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
In dichloromethane (200 ml) were dissolved 2,2′-thiodiethanol (10.0 g, 81.8 mmol) and imidazole (4.70 g, 69.0 mmol), followed by the dropwise addition of t-butylchlorodiphenylsilane (15.0 ml, 57.7 mmol) at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. After concentration under reduced pressure, diethyl ether was added to the residue. Then, the insoluble matter was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure, whereby the title compound (11.3 g, 31.3 mmol, 54%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:40])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:39])[C:17]([O:33][C@@H:34]([CH3:38])[CH2:35][O:36][CH3:37])=[C:18]([CH:32]=2)[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:12])=[C:4]([CH3:41])[CH:3]=1.CC1(C)C[O:47][B:46](B2OCC(C)(C)CO2)[O:45]C1.CC([O-])=O.[K+]>CS(C)=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]>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:14]([NH:13][C:11]([O:10][CH2:9][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([B:46]([OH:47])[OH:45])=[CH:3][C:4]=2[CH3:41])[CH3:40])=[O:12])[CH:15]=[C:16]([F:39])[C:17]=1[O:33][C@@H:34]([CH3:38])[CH2:35][O:36][CH3:37])[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: COC[C@H](C)Oc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(Br)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(B(O)O)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a reaction tube was added 37C (480 mg, 0.76 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (206 mg, 0.912 mmol), KOAc (186 mg, 1.900 mmol), Pd(dppf)Cl2 (125 mg, 0.152 mmol) in DMSO (1.5 ml). The tube was filled with Ar, sealed and stirred at 85° C. for 2 h. The mixture was quenched with water, and extracted with EtOAc. The combined organic layer was filtered though silica gel and concentrated. The crude product was purified by flash chromatography to give 37D (309 mg, 0.518 mmol, 68.2% yield). MS (ESI) m/z: 597.4 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:16]#[N:17])=[CH:10][CH:9]=1.Cl>C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:16][NH2:17])=[CH:10][CH:9]=1
Reactant: N#CC(Nc1ccc(Br)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC(Nc1ccc(Br)cc1)c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 47.4 %

Procedure:
Lithium aluminum hydride (52.9 mL, 52.9 mmol) in THF (1.0M) was added to a solution of 2-(4-bromophenylamino)-2-(4-chlorophenyl)acetonitrile (20.0 g, 62.2 mmol) in THF (311 mL, 62.2 mmol) at −78° C. The reaction was allowed to stir at −78° C. and gradually warmed to room temperature over 4 hours. The reaction mixture was poured into 1N HCl. The solution was then basified and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried and concentrated to give an oil. This residue was purified by column chromatography, eluting first with ethyl acetate/hexanes (2:1) then 5% MeOH/CH2Cl2→10% MeOH/CH2Cl2+1% NH4OH, affording N1-(4-bromophenyl)-1-(4-chlorophenyl)ethane-1,2-diamine as an oil (9.60 g, 49%). 1H NMR (400 MHz, CD3OD) δ □7.38 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 6.53 (d, 2H), 4.59 (dd, J=9.8, 4.7 Hz, 1H), 3.14 (dd, J=12.9, 4.7 Hz, 1H), 3.05 (dd, J=12.9, 9.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[C:23]([C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH:66]1[NH2:71]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[C:23]([C:28](=[O:29])[NH:71][CH:66]4[CH2:67][CH2:68][CH2:69][CH2:70][CH:65]4[CH3:64])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Reactant: CC1CCCCC1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
4-(5-Carboxy-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 46 (246 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (323 mg, 0.85 mmol) was added followed by diisopropylethyl amine (214 mg, 0.29 mL, 1.66 mmol) and 2-methyl-cyclohexylamine (71 mg, 0.63 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was charged to a flash column. Elution with 99:1 dichloromethane:methanol afforded 47 (380 mg) as a white foam that was contaminated with tetramethylurea, but suitable for use without further purification. 1H NMR (300 MHz, CDCl3) (1:1 mixture of diastereomers) 8 8.70 (m, 1H), 8.55 (d, 1H), 8.33 (d. 1H), 7.64 (m, 3H), 5.81 (d, 0.5H), 5.55 (d, 0.5H), 4.66 (d, 1H), 3.82 (m, 2H), 3.00 (m, 2H), 2.70 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.23 (m, 5H), 1.11 (d, 1.SF), 0.97 (d, 1.SH); LC/MS m/z 530 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[CH2:17][CH2:16][S:11]1
Reactant: CC(Br)Br
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 110 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g) , dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3- (3-trifluoromethylphenyl) thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room temperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3- (3-trifluoromethylphenyl) thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Yield: 22 %

Procedure:
(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (22% yield). HPLC: 98%, RT=3.556 min. MS: m/z=482 [M+H]+, RT=3.53 min. 1H-NMR (DMSO-d6) δ 10.34 (s, 1H), 9.73 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 7.41-7.36 (m, 5H), 7.29 (t, 1H), 7.15 (t, 1H), 7.09-7.06 (m, 4H), 6.78 (d, 1H), 6.74-6.68 (m, 1H), 6.50 (broad s, 2H), 6.41 (d, 1H), 3.93-3.92 (m, 2H), 2.78 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]([CH:17]([CH3:19])[CH3:18])[C:12]([O:14]CC)=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]([CH:17]([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)Nc1cccc(F)c1)C(C)C
Solvent: C1CCOC1
Product: CC(C)C(C(=O)O)C(=O)Nc1cccc(F)c1

Procedure:
Prepared according to procedure B using ethyl 2-(3-fluorophenylcarbamoyl)-3-methylbutanoate (5.2 g, 19.45 mmol) in THF (20 mL) to give 2-(3-fluorophenylcarbamoyl)-3-methylbutanoic acid as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=1[OH:22])(=[O:3])[CH3:2].S1[CH2:27][CH2:26]NC1>>[CH2:26]([O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=2[OH:22])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])[CH3:27]
Reactant: CC(=O)Oc1ccc(O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Reactant: C1CSCN1
Product: CCOC(=O)C1CSC(c2cc(OC(C)=O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for the preparation of 3-acetyl-2-(2-hydroxy-5-acetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid (4) was followed to prepare 12, except an ethyl ester of the thiazolidine was employed as starting material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=1/[CH:41]=[CH:42]/[C:43](O)=[O:44]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:43](=[O:44])[CH:42]=[CH:41][C:40]1[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=1[C:38]([F:50])([F:51])[F:37])[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccccc2C(F)(F)F)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 61.3 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-2-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) gave 37.6 mg (60%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(2-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.04 min; [M+H]+=682.49.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:33]1[CH:34]=[N:35]C(Br)=[N:37][CH:38]=1)[CH3:32]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:37]=[CH:38][C:33]([CH2:31][CH3:32])=[CH:34][N:35]=4)[CH2:19][CH2:20]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Reactant: CCc1cnc(Br)nc1
Product: CCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (50 mg, 0.12 mmol) and 5-ethyl-2-bromopyrimidine (29 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (37 mg, yield 73%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:17]=1>C(Cl)Cl.CCOC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:17][CH2:18][CH2:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(F)c(C2=NCCC2)c1
Reaction time: 2 h
Yield: 83.7 %

Procedure:
TFA (108 g, 940 mmol) was added to a solution of tert-butyl 5-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (53 g, 188 mmol) in DCM (300 mL) at 0° C. and stirring was continued at 20-35° C. for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with EtOAc, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulphate to afford 28.5 g of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)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>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2c(F)cccc2F)n1
Yield: 38 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2,6-difluorophenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,6-difluorophenyl)picolinic acid in 38% yield. LC/MS=236.0 (M+H), Rt=0.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(c1ccc2ccccc2c1)c1ccc(NS(=O)(=O)c2ccc(Cl)nc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 6-Chloro-pyridine-3-sulfonic acid [3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 55 mg, 0.12 mmol) in CH2Cl2 (2 mL), was added dropwise a solution of m-chloroperoxybenzoic acid (mCPBA, Aldrich, 36 mg, 0.12 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at ambient temperature for 1 hour and diluted with EtOAc (60 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (50 mL), twice with brine solution (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (10–25% EtOAc in hexane) to yield 17 mg (30%) of 103 as an off white solid.
Reaction SMILES: N1C=CN=C1.[S:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9].[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>CN(C=O)C.C(Cl)Cl.CCCCCC.CCOC(C)=O>[Si:24]([O:17][CH2:16][C@H:14]1[O:15][C@@H:7]([S:6][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:8]([OH:9])[C@@H:10]([OH:11])[C@@H:12]1[OH:13])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Imidazole (32 g) is added to a solution of 3 (30 g) in DMF (225 mL). After cooling to 0° C., tert-butyldiphenylsilyl chloride (34 g) is added. The reaction is allowed to come to room temperature overnight, whereupon TLC analysis (silica, 10% MeOH in CH2Cl2) indicates that the reaction is complete. MeOH (30 mL) is added and the reaction is stirred for an additional 30 minutes. The solvents are then removed in vacuo (40° C., 10 mm Hg). The residue is dissolved in EtOAc (500 mL) and washed successively with water (2×100 mL) and brine (2×100 mL). The EtOAc solution is then dried (MgSO4) and filtered. Removal of the EtOAc in vacuo provides a syrup which is subjected to flash column chromatography (silica, 5% EtOAc in hexane) to provide phenyl 6-O-(tert-butyldiphenylsilyl)-1-thio-β-D-glucopyranoside (4, 51 g).
Reaction SMILES: [OH-].[Li+].O.C([O:7][CH2:8][C:9]([NH:11][C:12]1[C:20]2[C:15](=[N:16][C:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:19]=2)[O:14][C:13]=1[C:36](=[O:41])[C:37]([OH:40])([CH3:39])[CH3:38])=[O:10])(=O)C.CO>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[C:20]3[C:12]([NH:11][C:9](=[O:10])[CH2:8][OH:7])=[C:13]([C:36](=[O:41])[C:37]([OH:40])([CH3:38])[CH3:39])[O:14][C:15]3=[N:16][C:17]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:22][CH:23]=1
Reactant: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CO
Temperature: 25 °C

Procedure:
Lithium hydroxide-H2O (0.004 g; 0.174 mmol), the product of Step C (0.100 g; 0.174 mmol), and methanol (0.3 mL) were combined in 2 mL of THF and stirred at room temperature. The reaction was monitored by TLC until complete at which point the reaction was quenched by addition of 0.50 mL of acetic acid. The reaction was diluted with ethyl acetate and then washed two times with aqueous sodium bicarbonate. The solution was concentrated and purified via MPLC chromatography on silica gel with a gradient elution of 0 to 50% ethyl acetate/hexanes. The product was further purified by recrystallization from ethanol to afford the title compound. HPLC/MS 534.8 (M+2); Rt=4.09 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([S:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[C:5]#[N:6].Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:4]([S:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)([CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:34]2)[C:5]#[N:6])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(C#N)(CCCl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(C#N)(CCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 12.1 %

Procedure:
The procedure of Example 3 is repeated using 3.3 g of α-(2-chloroethyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 1.14 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 0.311 g of the desired product as a brown oil. MS(FAB):m/z 519 (M+H). Calcd for C30H34N2O4S 0.5H2O: C=68.28, H=6.99, N=5.31, S=6.80 Found C=68.56, H=6.55, N=5.21, S=5.73
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][C@H:3]1[C:9](O)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>CCOCC>[CH3:1][C:2]1([CH3:12])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: CC(C)=C1C[C@@H](C(=O)O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)=C1C[C@@H](CO)C1(C)C

Procedure:
With methylethylidene compound 5 in hand the remaining steps were as follows: The resulting acid 5a was treated with LiAlH4 in ether to furnish the (R)-(−)-maconelliol 6a {[α]24D−31.0 (c 0.1, MeOH)} in good yield, and its enantiomeric purity was determined to be 78% ee. Similarly, (1S)-(−)-verbenone (80% ee, commercially available) was also converted into (S)-(+)-maconelliol 6b {70% ee, [α]24D+22.0 (c 0.1, MeOH)}. The various spectral and GC data of synthetic (R)-(−)-6a were in good agreement with those of the natural product (Zhang, A., et al., Proc. Natl. Acad. Sci. U.S.A., 101: 9601-9606 (2004)). Thus, we were able to determine the absolute configuration of the naturally occurring maconelliol 6 to be R.
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br)(=[O:16])=[O:15])[CH:11]=[CH2:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>>[C:1]([O:9][CH:10]1[CH2:11][CH2:12][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:14](=[O:16])(=[O:15])[CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(CS(=O)(=O)c1ccccc1Br)OC(=O)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Product: O=C(OC1CCc2ccccc2S(=O)(=O)C1)c1ccccc1

Procedure:
In Synlett, 9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-1-buten-4-yl sulfone was treated with tributyl tin hydride and AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1-dioxide.