Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([CH3:40])(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3S(C)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Temperature: 65 °C
Yield: 79.2 %

Procedure:
A stirred mixture of 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.1073 g, 0.403 mmol) and 2-(2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (228 mg, 0.607 mmol) in tetrahydrofuran (5 ml) and 2M aqueous sodium carbonate (containing 1 ml/l of 40 wt % tetrabutylammonium hydroxide in water) (0.605 ml, 1.21 mmol) was degassed by bubbling nitrogen through the mixture for 15 min. Tetrakis(triphenylphosphine)palladium(0) (24.6 mg, 0.0213 mmol) was then added and the mixture was heated at 65° C. under nitrogen for 6 h. After cooling, the mixture was partitioned between ethyl acetate (25 ml) and water (15 ml). The aqueous layer was extracted further with ethyl acetate (2×25 ml) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (40-50%), to afford 3-[2-fluoro-2′-(methanesulfonyl)biphenyl-5-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid (139 mg, 79%): mp 211-213° C. (ethyl acetate/isohexane); δH (360 MHz, CDCl3) 2.89 (3H, s), 7.27 (1H, d, J 6.9), 7.40 (1H, td, J 1.2, 9.0), 7.46 (1H, dd, J 1.2, 7.4), 7.62-7.66 (2H, m), 7.68 (1H, td, J 1.6, 7.4), 7.74 (1H, td, J 1.6, 7.4), 8.10 (1H, s), 8.29 (1H, dd, J 1.4, 8.0), 9.22 (1H, d, J 7.0); MS (ES+) m/z 436 [M+H]+. Anal. Found: C, 55.02; H, 3.02; N, 9.23%. Required for C20H13F4N3O2S.0.1H2O: C, 54.94; H, 3.04; N, 9.61%.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[CH3:15][NH:16][CH2:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26]O)[OH:25])[OH:23])[OH:21])[OH:19]>C(O)C>[CH3:15][N:16]([CH2:17][C@H:18]([OH:19])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]([OH:25])[CH3:26])[C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([N:16]([CH3:15])[CH2:17][C@H:18]([OH:19])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]([OH:25])[CH3:26])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CN(C)C(=O)c1cnc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@@H](C)O)cn1
Yield: 102 %

Procedure:
A solution of 392 mg of 2,5-dimethoxycarbonylpyrazine and 780 mg of N-methylglucamine in 5 cm3 of ethanol is heated at a temperature close to the reflux temperature for 3 hours and the reaction mixture is filtered while hot. The white solid is washed with twice 10 cm3 of boiling ethanol. 1000 mg of N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5-tetrahydroxy-1-hexyl]-N′-methyl-N′-[(2S,3R,4R,5R)-2,3,4,5-tetrahydroxy-1-hexyl]-pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 152° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, at a temperature of 403 K, δ in ppm): 3.14 (s, 6H: 2×NCH3); from 3.45 to 4.28 (mts, 16H: 8×CHO−2×CH2 and 2×CH2N); 8.78 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:13]=2[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([O-:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:13]=2[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
2-[2-(4-Chlorophenylsulfonamido)-4-trifluoromethylphenoxy]benzoate was mixed in methylene chloride (5 mL) at 0° C. for 5 min. Trifluoroacetic acid (5 mL) was then added dropwise to the cold mixture and stirred for 2 h. The solvents were evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound; mp 164° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CCO.[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24]2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC(C)(C)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a round-bottomed flask was added methyl 4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoate (25) (8.06 g, 21 mmoL), EtOH (100 mL), and THF (100 mL). To the solution was added 1 N aqueous NaOH (200 mL). The reaction mixture was stirred at 65° C. under a nitrogen atmosphere for 3 h. The reaction mixture was partially concentrated in vacuo to remove the EtOH and THF. The aqueous mixture was cooled in an ice-water bath and 1 N aqueous HCl was slowly added to pH ˜1. The acidic aqueous suspension was extracted with CH2Cl2 (1 x) followed by EtOAc (3 x). Those EtOAc extracts that contained the majority of product, as indicated by TLC, were independently washed with brine, combined, dried over MgSO4, filtered, and the filtrate was concentrated to give 6.0 g of the crude product as a pale tan solid. The CH2Cl2 extract noted above was concentrated to give 1.9 g of the crude product as an off-white solid. The two crops of crude product were combined and purified by flash chromatography on silica gel with CH2Cl2:MeOH (95:5) to give 6.07 g (79%) of compound 26 as a white solid. A portion of the product was dried under vacuum at 90° C. to give the following 1H NMR data. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.88 (s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.92 (s, 2H), 6.66 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.30 (s, 2H), 12.78 (br s, 1H). The compound was silylated prior to EI analysis. HRMS (EI) Calcd for C30H44O3Si2: 508.2829 (M+). Found: 508.2833.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=[O:32])[CH2:24][CH:23]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:34])[CH2:29][CH2:30][C:31]([NH:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[O:32])[CH2:24][CH:23]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)cc1
Yield: 99.5 %

Procedure:
A mixed solution of 169 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoic acid, 54 mg of methyl 4-aminobenzoate, 61 mg of WSC/hydrochloride, 45 mg of HOBt, and 2.00 mL of DMF was stirred at room temperature for 2 hours, and a saturated aqueous sodium hydrogen carbonate solution was added thereto. It was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 208 mg of methyl 4-({4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoate as a pale brown oily compound. ESI+: 696
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH:13]=[CH:12][C:11]=12.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH:13]=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc3nccn3c2)cc1
Reactant: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CCNC(=O)c1ccc(C(=O)NCc2ccc3nccn3c2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting 3-methylbutan-1-amine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.15 (t, J=5.8 Hz, 1H), 8.55-8.47 (m, 2H), 8.00-7.84 (m, 5H), 7.54 (dd, J=5.1, 4.1 Hz, 2H), 7.23 (dd, J=9.3, 1.7 Hz, 1H), 4.48 (d, J=5.8 Hz, 2H), 3.30-3.21 (m, 2H), 1.62 (dp, J=13.3, 6.6 Hz, 1H), 1.49-1.37 (m, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 365 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:11]([O:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17]([CH3:19])=[CH2:18])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH2:11]([O:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17]([C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:19])[CH3:18])[CH3:12]
Reactant: Brc1ccc2c(c1)CCO2
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F

Procedure:
4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester was prepared using the procedure described in Example 1 with 5-bromo-2,3-dihydrobenzofuran and 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in carbon disulfide with aluminum chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6](Br)[CH:5]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(OC)c(-c2ccc(OC)c(F)c2)c1
Yield: 84.4 %

Procedure:
3-Bromo-4-methoxybenzoic acid methyl ester (500 mg, 2.04 mmol), 3-fluoro-4-methoxyphenylboronic acid (381 mg, 2.24 mmol), Tetrakis(triphenylphosphine)-palladium(0) (117 mmol, 0.10 mmol), and sodium bicarbonate (514 mg, 6.12 mmol) were partitioned between toluene (5 ml) and water (5 ml) and stirred in reflux for 36 hours. The mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium sulfate and evaporated to dryness. The raw material was purified by silica gel chromatography with a heptane/ethyl acetate gradient. to yield the title compound (500 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[C:22]([O-])([O-])=O.[K+].[K+].C=O>CO.C(Cl)Cl>[CH2:10]([C:9](=[CH2:22])[C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:2]([F:1])[CH:7]=1)=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Agent: C=O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C=C(CCCC)C(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 105.2 %

Procedure:
A solution of N-(2-fluoro-4-hexanoylphenyl)-2,2-dimethylpropanamide (17.8 g, 60.7 mmol) in methanol (75 mL) was treated successively with K2CO3 (8.4 g, 60.7 mmol) and formaldehyde (37 wt. % solution in water, 5.0 mL, 67 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 55° C. for 4 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (300 mL), dried over MgSO4, and filtered through a pad of silica gel, using more CH2Cl2 (200 mL) to wash the pad. The filtrate and washings were concentrated under vacuum to provide a mixture (19.5 g) of N-[4-(2-butylacryloyl)-2-fluorophenyl]-2,2-dimethylpropanamide, N-{2-fluoro-4-[2-(hydroxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide, and N-{2-fluoro-4-[2-(methoxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide.
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:6][OH:7].C([Mg:15][Cl:16])CCC.CCCC>C(Cl)CCC>[CH3:4][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:6][O:7][Mg:15][Cl:16]
Reactant: CCCC[Mg]Cl
Reactant: CCCC(C)CO
Agent: II
Agent: [Mg]
Solvent: CCCCCl
Solvent: CCCC
Product: CCCC(C)CO[Mg]Cl
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Following the procedure of Example 1, 24.31 gm of magnesium metal powder (1.0 mole) was placed in a 3-necked 3 liter reactor flask, along with 1600 ml of isoparaffinic solvent (Isopar E) having a boiling range of 116°-139° C. and 0.25 gm of iodine crystals. This mixture was heated under an argon atmosphere to reflux temperature for about 60 minutes for metal activation. 105 ml of n-butyl chloride (1.OM) was then gradually added to the reaction slurry in 40 minutes, then reaction was continued for two hours at reflux temperature. Addition of 180 ml (1.4 moles) of 2-methyl-1-pentanol to the reaction slurry was started. The reaction slurry became thick and viscous at reflux temperatures when 60 ml of the 180 ml of the 2-methyl-1-pentanol was added. At this point the reaction slurry was cooled down to 65° C. At 65° C. the remaining 120 ml of 2-methyl-1 -pentanol was added along with 400 ml of solvent (Isopar E) with good agitation to reduce the viscosity of the slurry. The 2-methyl-1-pentanol reacted with BuMgCl as was evidenced by the release of butane. Butane was distilled off through reflux condensor to maintain the reaction temperature close to the reflux temperature of solvent Isopar E. The reaction was continued for two hours. The slurry was filtered while hot, 90°-100° C. The filtration rate was fast and complete in about 10-15 minutes. Final volume of filtrate was about 2100 ml. Fine gray suspended particles as solid were collected on the filter. The clear filtrate was analyzed and found to have 0.435 molar magnesium concentration with 91.40+% magnesium recovery. This filtrate was found to be stable at 0° to 40° C. on storage.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].C1(C)C=CC=CC=1.C1(C(O)=O)CC1.C1(C)C=CC(S(O[CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:38]=2)(=O)=O)=CC=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:38]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C1CC1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
Cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (22 g, 0.105 M) was added to a solution of an inorganic base in water (50 ml). Toluene (100 ml), tetra-n-butylammonium bromide (1.6 g, 5 mole % based on the cyclopropane carboxylic acid) and alpha-cyano-3-phenoxybenzyl p-toluenesulphonate (37.9 g, 0.1 M) were added to the stirred mixture which was then heated at 40°-45° C. for 24 hours. The reaction mixture was then treated as in Example 1 to yield cis-alpha-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate as a pale amber oil containing less than 1% trans-isomers.
Reaction SMILES: Br[CH:2]([C:16](=O)[CH3:17])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][C:16]1[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26][C:2]=1[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: CC(=O)C(Br)CCN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
To a solution of 2-(3-bromo-4-oxo-pentyl)-isoindole-1,3-dione (12.4 g) [CAS 112357-34-3] in abs. DMF (50 ml) was added benzamidine 85% (5.65 g) and potassium carbonate (11.03 g). The reaction mixture was stirred at 80° C. for 4 h, concentrated under vacuum. To the residue was added ice/water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate and concentrated. The crude product was purified by chromatography on silica gel using methylene chloride/methanol 5% and 10% as eluent to obtain 2-[2-(5-methyl-2-phenyl-1H -imidazol-4-yl)-ethyl]-isoindole-1,3-dione (5.5 g) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[C:13](OC(=O)C)(=O)C.[OH-].[Na+].S(OC)(OC)(=O)=O.Cl.[Cl-].[Na+]>O.C(O)=O>[CH3:13][NH:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10])[NH2:1]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: O=CO
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
94 g of 1,3-diaminobenzene-4-sulfonic acid in 430 ml of water and 70 g of formic acid were boiled for 3 hours under reflux. The mixture was cooled to 20° C., and the resulting 3-(N-formylamino)aniline-4-sulfonic acid was filtered off in vacuo and stirred in 500 g of water with the addition of caustic soda solution to give a pH of 6.5. 70 g of acetic anhydride were then added and the pH was kept between 5.0 and 6.5 by the addition of caustic soda solution. After 30 minutes, the pH was adjusted to 12.5 with caustic soda solution, and 75 g of dimethyl sulfate were added dropwise. After 30 minutes, the pH was adjusted to -0.5 with hydrochloric acid, and the mixture was boiled under reflux for 3 hours. After cooling, the mixture was adjusted to pH 1.0 with caustic soda solution and salted out with 150 g of sodium chloride. The precipitated 3-(N-methylamino)aniline- 4-sulfonic acid was isolated by filtration in vacuo.
Reaction SMILES: [Li]CCCC.[CH3:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.Cl.N>C1COCC1>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][C:21]=2[CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[CH3:6])[CH:26]=[CH:27][CH:18]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: CC1Cc2ccccc2C1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=Cc2ccccc2C1c1cccc2cccnc12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
6.70 ml of n-BuLi (16.8 mmol) were added dropwise at 100° C. to 3.50 g of o-bromoquinoline (16.8 mmol) dissolved in 50 ml of THF, and the mixture was subsequently stirred at 80° C. for 15 minutes. A solution of 50 ml of THF and 2.45 g of 2-methyl-1-indanone (16.8 mmol) was then added to the lithiated bromoquinoline over the course of 10 minutes. The mixture was allowed to cool to room temperature, and the solution was then refluxed for three hours, cooled to room temperature, acidified to pH 1 using ice and hydrochloric acid and subsequently refluxed for three hours. The reaction mixture was adjusted to pH 9 using ammonia solution, and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried, and the solvent was removed. The crude product was purified by distillation under reduced pressure at 150-160° C./10−2 mbar, giving 1.5 g of 1-(8-quinolyl)-2-methylindene (45%) as a yellow, viscous resin.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]([NH:14][CH:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][C:17]([O:19]CC)=[O:18])=[O:13])=[CH:6][CH:5]=1.[OH-].[Li+]>CO>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]([NH:14][CH:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(NC(=O)CCNCc1ccc(C=NN)cc1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NN=Cc1ccc(CNCCC(=O)NC(CC(=O)O)c2cccnc2)cc1
Yield: 76.9 %

Procedure:
Ethyl β-[[3-[4-(aminoiminomethyl)benzyl]aminopropanoyl]amino]3-pyridine-propanoate (70 mg) was treated with 1N lithium hydroxide and methanol (1:1; 20 ml) for 5 min. Methanol was removed under reduced pressure and the residue was purified by HPLC using acetonitrile/water/trifluoroacetic acid system. The desired fractions were collected and lyophilized to give 50 mg of white material (77% yield). FAB-MS: MH+ =370.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[NH:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Br>CN(C=O)C>[Br:11][C:8]1[N:7]([CH2:23][C:22]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:21]=2[Cl:20])[C:6]2[C:5](=[O:12])[NH:4][C:3](=[O:13])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1c(F)cccc1Cl
Temperature: 60 °C
Yield: 76 %

Procedure:
A solution of 3-methyl-8-bromoxanthine (1.5 g, 6.1 mmol, Klein, J. P. PCT Int. Appl. WO 0061583, 2000) and K2CO3 (0.84 g, 6.1 mmol) in 6 mL DMF was treated with 2-chloro-6-fluorobenzyl bromide. The reaction mixture was heated to 60° C. for 2 hr, cooled, and poured onto ice water. The solid precipitate was filtered and dried to yield 1.8 g (76% yield) of a white solid: 1H NMR (DMSO, 400 MHz) 7.43-7.36 (m, 1H), 7.34-7.30 (m, 1H), 7.22-7.15 (m, 1H), 5.67 (s, 2H), 3.29 (s, 3H); MS (AP+) m/e 389 (MH+).