Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]2[CH:12]=[N:13][C:14]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])=[C:6]2[CH2:5]1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1>>[CH3:24][C:2]([CH3:23])([CH3:1])[CH2:3][N:4]1[CH2:9][C:8]([CH3:10])([CH3:11])[N:7]2[CH:12]=[N:13][C:14]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:34](=[O:35])[CH2:33][C:28]3[CH:27]=[C:26]([F:25])[CH:31]=[C:30]([F:32])[CH:29]=3)[CH2:18][CH2:19][CH3:20])=[C:6]2[CH2:5]1
Reactant: CCCC(N)C(=O)Nc1ncn2c1CN(CC(C)(C)C)CC2(C)C
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1ncn2c1CN(CC(C)(C)C)CC2(C)C

Procedure:
Following general coupling procedure A, 2-amino-pentanoic acid [7-(2,2-dimethyl-propyl)-5,5-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl]-amide is coupled with (3,5-difluoro-phenyl)-acetic acid to provide the title compound: Diagnostic C13 NMR (100 MHz, CDCl3) 13.5, 18.9, 27.4, 28.1, 28.6, 33.5, 35.4, 43.1, 52.8, 53.2, 56.2, 65.7, 69.9, 102.9, 112.3, 112.6, 117.4, 129.2, 169.9; MS m/z 490.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C=O)o2)c1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)c1

Procedure:
3-Benzyloxy-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-04) (1.6 g, crude) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (11-04) (1.8 g, 4.35 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:3]=1[CH2:4][N:5]([CH2:15][C:16](OCC)=[O:17])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:27]1([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH:30]=[CH:29][CH2:28]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl.[OH-].[Na+].C(O)C.C(OCC)(=O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([N:5]2[CH2:4][C:3]3[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:2]=3[N:1]([CH2:38][C:37]3[CH:36]=[CH:35][C:34]([C:32]([N:27]4[CH2:31][CH:30]=[CH:29][CH2:28]4)=[O:33])=[CH:41][CH:40]=3)[C:16](=[O:17])[CH2:15]2)=[O:14])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Reactant: CCOC(=O)CN(Cc1c(N)cccc1OC)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc2c1CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
243 mg (0.65 mmol) of ethyl [(2-amino-6-methoxybenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in 5 ml of dichloromethane. 156 mg (0.78 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)-benzaldehyde and 0.074 ml (1.3 mmol) of acetic acid were added to the obtained solution, and they were stirred at room temperature for 30 minutes. 340 mg (1.6 mmol) of sodium triacetoxyborohydride was added to the reaction mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in a mixture of 2 ml of 1 N sodium hydroxide and 10 ml of ethanol, and the obtained solution was stirred at room temperature for 5 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 5 ml of dichloromethane. 131 mg (0.78 mmol) of 2-chloro-1,3-dimethyl-imidazonium chloride and 0.19 ml (1.3 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])[CH3:12])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]2[CH:21]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P(=O)(O)(O)O.[K]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:16]([C:13]([CH3:15])([CH3:14])[C@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:21]=[C:2]([C:27]3[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:18]([NH2:20])=[O:19])[CH3:12])#[N:17]
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C#N
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)C#N)c(C(N)=O)cnn3c2)cn1
Temperature: 135 °C
Yield: 68.5 %

Procedure:
To a mixture of (R)-6-bromo-4-((3-cyano-3-methylbutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (160 mg, 0.457 mmol), (6-methoxypyridin-3-yl) boronic acid (105 mg, 0.685 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21.78 mg, 0.046 mmol), palladium(II) acetate (5.13 mg, 0.023 mmol) and phosphoric acid, potassium salt (291 mg, 1.371 mmol) taken in 1,4-dioxane (2 mL) and water (0.2 mL) in a pressure tube (15 mL). The reaction mixture was degassed using nitrogen and then heated to 135° C. for 45 min. Reaction was monitored by LCMS. Reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried and concentrated under reduced pressure to get crude as brown colored oil. The crude was purified by combiflash using 24 g silicycle column eluted with 70% ethyl acetate in hexane. The fractions were concentrated under reduced pressure to get (R)-4-((3-cyano-3-methylbutan-2-yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (120 mg, 0.313 mmol, 68.4% yield) as off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.15-11.13 (d, J=9.6 Hz, 1H), 8.71-8.70 (d, J=2.4, 1H), 8.277-8.25 (t, J=8.8 and 1.2, 2H), 8.196-8.168 (dd, J=2.4 and 2.8 Hz, 1H), 7.41-7.40 (bs, 2H), 6.89-6.87 (d, J=8.4 Hz, 1H), 4.63-4.56 (m, 1H), 3.89 (s, 3H), 1.46-1.41 (m, 9H). HPLC purity: Column: Xbridge phenyl (4.6×150 mm, 3.5 μm), Buffer: 0.05% TFA in H2O (pH 2.5, adjusted with dilute ammonia), Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 25-100, 30-100 min, Flow: 1.0 mL/min Retention Time: 11.88: Purity: 98.6%. CHIRAL HPLC purity: Column: CHIRALPAK IC (250×4 6 mm) 5 micron, Mobile Phase: 0.2% DEA in Hexane:Ethanol (70:30). Flow: 1.0 mL/min: Retention Time: 10.138. Purity: 95%. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90). Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.605 min. Purity: 99.14% (m/z=379.2 M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CS(O[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Product: CS(=O)(=O)CCN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-({(2S)-1-[2-(methylsulfonyl)ethyl]pyrrolidin-2-yl}methyl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-(methylsulfonyl)ethyl methanesulfonate (prepared as described in WO 2006/047277) following General Procedure S.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:27])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCOCC1
Reactant: COc1ccc(-c2c(-c3nc(CCC(=O)O)cs3)cnn2C(C)(C)C)cc1
Product: COc1ccc(-c2c(-c3nc(CCC(=O)NC4CCOCC4)cs3)cnn2C(C)(C)C)cc1

Procedure:
Using the compound obtained in step 1 and 4-aminotetrahydropyran and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C.[C:45]([NH:55][C@H:56]([C:60](O)=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>ClCCl>[C:45]([NH:55][C@H:56]([C:60]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:10])=[O:61])[CH:57]([CH3:59])[CH3:58])([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: COc1ccc(COC(=O)Cc2ccccc2O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Cc2ccccc2OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Yield: 93.5 %

Procedure:
4-Methoxybenzyl 2-hydroxyphenylacetate 3 g, 11 mmol), N,N,-dichyclohexyl-carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine (0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolved in dichloromethane (50 ml). After the weekend the solid was filtered off, the solvent removed under reduced pressure and the crude product purified by chromatography (ethyl acetate, hexane, 1:2) to give the title compound (5.2 g, 93%).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Li]C(CC)C.C[O:18]B(OC)OC.OO.[OH-].[Na+]>C1COCC1.C1CCCCC1>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:18])[C:5]=2[O:6]1
Reactant: COB(OC)OC
Reactant: FC1(F)Oc2ccccc2O1
Agent: OO
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Oc1cccc2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
2,2-Difluoro-1,3-benzodioxole (320 mg, 2.05 mmol) was dissolved in THF (2.5 mL) and cyclohexane (1.2 mL) and the resulting solution cooled down to −78° C. sec-BuLi 2M solution in cyclohexane (1.025 ml, 2.05 mmol) was added drop wise and the reaction mixture stirred for 2 hours at −78° C. Trimethylborate (230 mg, 2.25 mmol) was added and the mixture was allowed to warm slowly to room temperature. A 30% w/w aqueous solution of H2O2 (4.1 mmol) and NaOH (82 mg, 2.05 mmol) were added and the reaction mixture stirred for 18 hours at room temperature. The reaction was quenched with a 2N aqueous solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness, affording the title compound (340 mg).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].CS[C:16]1[S:20][CH:19]=[CH:18][S+:17]=1>O1CCCC1>[Cl:9]([O-:13])(=[O:12])(=[O:11])=[O:10].[S:17]1[CH:18]=[CH:19][S:20][C:16]1=[N+:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4]
Reactant: CSc1scc[s+]1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1CCC[N+]1=c1sccs1
Temperature: 25 °C

Procedure:
To 80 ml of tetrahydrofuran, 1.0 g of proline was suspended, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture comprising 50 ml of water and 50 ml of ethyl acetate. The aqueous layer was separated and the solvent was distilled off under reduced pressure, whereby 1.6 g (yield: 63%) of 1-(1,3-dithiol-2-ylidene)-2-carboxypyrrolidinium perchlorate (Compound No. 43) was obtained as yellow oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12](O)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.P(Cl)(Cl)([Cl:19])=O.CN(C)C=O>>[Cl:19][C:12]1[N:13]=[C:14]2[C:5](=[C:6]3[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:4]=[CH:3][C:2]([F:1])=[CH:15]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cc(F)ccc2c2ccccc12
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)nc(Cl)c1ccccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 3-fluorophenanthridin-6-ol (Example 1a, 1.58 g, 7.41 mmol) in phosphorus oxychloride (11.7 g, 7.1 mL, 76 mmol) was added dimethylformamide (0.34 g, 0.46 mmol), and the reaction mixture was warmed to 65° C. and stirred under nitrogen for 1 h. The reaction mixture was cooled to room temperature, followed by the careful addition of ice to the reaction mixture. The mixture was stirred for 20 min, and the extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to provide the title compound (1.2 g, 70% yield), which was used without further purification.
Reaction SMILES: [C:1]1(=O)OC(=O)C=C1.C(O)(=O)/C=C\C(O)=O.[C:16]([O:23][CH3:24])(=[O:22])/[CH:17]=[CH:18]\[C:19]([O-:21])=[O:20]>CO>[C:19]([O:21][CH3:1])(=[O:20])/[CH:18]=[CH:17]\[C:16]([O:23][CH3:24])=[O:22]
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: COC(=O)/C=C\C(=O)OC

Procedure:
A butane oxidation reactor produces 100 moles per hour of maleic anhydride, of which 40 kmols are condensed by cooling the gases in condensers. The remaining 60 moles per hour are recovered as a 50 wt % aqueous solution of maleic acid from an absorber. This is fed to an evaporation system to concentrate the solution of maleic acid. The concentrated solution is fed to a dehydration reactor system to produce a stream of crude maleic anhydride. This maleic anhydride, together with the crude maleic anhydride from the partial condensers is fed to an esterification unit. The crude maleic acid is mixed with recycle methanol from the refining section and fed to a plug flow, mono-ester reactor. The product from this is fed to a reaction column to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 mols per hour of methanol are fed to the bottom of the reaction column. Essentially dry, fully converted di-methyl maleate is fed to hydrogenation. Recycle methanol from the refining section is fed to the top of the reaction column as washed to minimise the di-methyl maleate in the overhead of the column.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:4]([OH:6])=[O:5].CO.C(Cl)(Cl)Cl.[AlH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>O.C(O)C.C(Cl)Cl>[CH3:1][O:2][CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:4]([O-:6])=[O:5].[AlH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCOCCOC(OC)C(=O)O
Agent: C1CC[AlH]OC1
Solvent: CCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCCOC(OC)C(=O)[O-]
Temperature: 1100 °C
Reaction time: 1 h

Procedure:
Pseudoboehmite (20.0 g) and methoxy(ethoxyethoxy)acetic acid (102 mL) were refluxed in water (400 mL) resulting in a clear solution after 72 h. The solution was centrifuged at 6000 rpm for 1 hour and decanted. Removal of the volatiles in vacuo (10−2 Torr) at 90° C. yielded a gel which was then dissolved in ethanol (100 mL) while stirring (10 min.) then triturated with diethyl ether (200 mL). The white solid powder thus obtained was redissolved in water (100 mL) and dried at 50° C. for 24 h resulting in a clear glassy material. The MEEA-alumoxane is soluble in water, methanol, chloroform, and methylene chloride. The alumoxane was heated from 25° C. to 225° C. at the rate of 1° C./min., soaked for 30 mins. at 225° C., followed by a temperature ramp up to 300° C. at the rate of 2° C./min., and soaked for 80 mins., with a final ramp to the maximum temperature of 1100° C. (over 360 minutes) which was then maintained for 400 minutes (FIG.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([CH:9]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)O)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH:6]1([C:9](=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH2:8][CH2:7]1
Reactant: CCCCOC(=O)C(C1CC1)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
Phosphorous oxychloride (1 mL) was added slowly to a solution of butyl 2-cyclopropyl-3,3-bis(4-fluorophenyl)-3-hydroxypropionate (0.2 g, 0.53 mmol) in 4.5 mL of pyridine at -10° C. After stirring for 18 hours at 25° C., the mixture was heated at 100°-110° C. for 1.25 hours. The mixture was poured over ice and extracted with diethyl ether. The extracts were dried with magnesium sulfate to give 0.15 g of the title compound as an oil. MS(FAB): m/e =356 for M+ of C22H22F2O2.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][O:40]C(=O)C2C=CC=CC=2)=[CH:34][CH:33]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][OH:40])=[CH:36][CH:37]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cnccc2Cc2ccc(CCOC(=O)c3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCc1ccc(Cc2ccncc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 86.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[4-(2-benzoyloxyethyl)benzyl]pyridine (0.086 g) in methanol (1 mL) was added sodium methoxide (28% solution in methanol, 0.008 mL), and the mixture was stirred for 23 hours at 25° C. After the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=4/1) to give 3-(β-D-glucopyranosyloxy)-4-[4-(2-hydroxy-ethyl)benzyl]pyridine (0.044 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2.[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][NH:31]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].CC(C)([O-])C.[Na+]>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].[Pd].C1(P[C-]2C=CC=C2)C=CC=CC=1.[C-]1(PC2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][N:31]2[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH:7]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
3-sulfonyl-8-iodo quinoline (D6) (200 mg, 0.48 mMol), (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (95 mg, 0.48 mmol), sodium tbutoxide (65 mg, 0.68 mmol), di-palladium tetrakis-(dibenzylidene acetone) (88 mg, 0.1 mmol) and 1,1′-diphenylphosphino ferrocene (161 mg, 0.3 mMol) were suspended in degassed dry dioxan (2 ml). The mixture was stirred under argon at 40° C. for 16 hours. The solvent was removed and the residue was purified by chromatography on silica using 30% ethyl acetate in hexane to afford (1S,4S)-5-(3-benzenesulfonyl-quinolin-8-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 70% yield. This material (160 mg) was treated with 4M hydrochloric acid (1 ml) and dioxan (1 ml) with stirring at 80° C. for 30 mins. The solvent was removed to afford the title compound (E43) as a yellow solid;
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10]O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.C(#N)C>[I:39][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-(−)-N-Boc-prolinol (10 g, 49.7 mmol), imidazole (6.76 g, 99.4 mmol) and triphenylphosphine (19.5 g, 74.5 mmol) were dissolved in diethyl ether (210 ml) and acetonitrile (80 ml) and the solution was cooled to 0° C. under an inert gas. Iodine (17.7 g, 70 mmol) was added in portions at this temperature. The yellow suspension was stirred for 15 h, and warmed to room temperature during this procedure. Addition of sodium thiosulfate solution (50 ml, 5 mol/l), stir for 5 min, the phases were separated. The aqueous phase was extracted with diethyl ether (2×100 ml) and the combined organic phases were washed with copper sulfate solution (30 ml, 5%) and sodium chloride solution (30 ml, saturated), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (6:1). Yield: 10.57 g (68%)
Reaction SMILES: C([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=O)C.F[C:11](F)(F)[C:12](O)=[O:13]>>[C:12]([C:7]1[CH:8]=[CH:4][N:5]([CH3:9])[CH:6]=1)(=[O:13])[CH3:11]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1cccn1C
Product: CC(=O)c1ccn(C)c1

Procedure:
A solution of 3.0g of 2-acetyl-1-methylpyrrole in 30 ml of trifluoroacetic acid is heated under reflux for 90 minutes. The solvent is then evaporated in vacuo and the residue is partitioned between chloroform and sodium bicarbonate solution. The chloroform layer is dried and the solvent evaporated in vacuo to give 3-acetyl-1-methylpyrrole as a brown oil.