Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C2CCCCO2)=[O:21])[C:13](=[O:35])[CH:12]=1.O>O1CCOCC1.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=1
Reactant: CC(CCn1ccc(-c2cc3ccccc3o2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(CCn1ccc(-c2cc3ccccc3o2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (5 mL) was added slowly to a solution of (+/−)-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (105 mg, 0.22 mmol) in dichloromethane (5 mL) with water (1.0 mL) at 0° C. The ice bath was removed and the reaction was allowed to warm to rt. After 30 min (complete by TLC), the reaction was concentrated to afford a crude white solid. The crude was triturated in isopropanol (5 mL) overnight. The solid was collected via filtration, washed with isopropanol (5 mL), isopropanol:heptane (1:1, 5 mL), heptane (5 mL), and ether (5 mL). The solid was collected by filteration and dried under vacuum to afford a white solid (86.1 mg, 99%). LC-MS m/z 405.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.10-2.23 (m, 1 H) 2.39-2.48 (m, 1 H) 3.11 (s, 3 H) 3.71-3.81 (m, 1 H) 4.05-4.15 (m, 1 H) 6.78-6.89 (m, 2 H) 7.27-7.35 (m, 1 H) 7.37-7.45 (m, 1 H) 7.63-7.82 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[CH2:14][S:15]CC1C=CC(OC)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[CH2:14][SH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CSCC2NC(=O)C2NC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1C(=O)NC1CS
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To a solution of 335 mg (0.95 mmole) of 3t-butoxycarbonylamino-4-oxo-2-(p-methoxybenzylthiomethyl)azetidine in 5 ml of methanol and 20 ml of methylene chloride is added 1.7 g (5.3 mmole) of mercuric acetate. The mixture is stirred 24 hours under argon, diluted with excess ether and the precipitated mercury adduct filtered and washed well with ether. The mercury complex is suspended in water, layered with ethyl acetate and hydrogen sulfide gas is passed through the mixture for 1 hour. The mercuric sulfide is removed by filtration, the ethyl acetate layer is separated and washed with brine, dried over magnesium sulfate and evaporated to dryness. Trituration of the residue with 1:1 ethyl acetate-hexane gives 122 mg (55%) of the crystalline title product.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][N:25]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].CO>CO>[ClH:34].[ClH:34].[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](/[CH:23]=[CH:22]/[C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[O:33])=[CH:21][CH:20]=2)=[N:25]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCCNCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of Compound 82 (100 mg, 0.224 mmol) in methanol (10.0 mL) was added with 10% hydrogen chloride-methanol solution (10.0 mL), followed by stirring at 60° C. for 2 hours. After cooling to room temperature, deposited crystal was collected by filtration to obtain Compound 85 (48.7 mg, 47%).
Reaction SMILES: O=C(Cl)OC(Cl)(Cl)Cl.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:26][C@H:27]1[C@@H:30]([S:31]([CH3:34])(=[O:33])=[O:32])[NH:29][C:28]1=[O:35].C1OC1C>C(Cl)Cl.CC(N(C)C)=O.C(N(CC)CC)C.CN(C=O)C>[Cl:9][CH2:10][C:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH3:25])[C:20]([NH:26][C@H:27]2[C@@H:30]([S:31]([CH3:34])(=[O:33])=[O:32])[NH:29][C:28]2=[O:35])=[O:22])[N:18]=1)=[O:12]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1N
Agent: CC1CO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1S(C)(=O)=O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 0.122 g of DMF in 5 ml of methylene chloride is added 0.10 ml of diphosgene at -10° C. The mixture is stirred for 30 minutes at room temperature, then cooled to a temperature of -70° C., followed by dropwise addition of 10 ml of methylene chloride solution containing 0.427 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid and 0.17 g of triethylamine. The mixture is stirred for 2 hours at a temperature ranging from -25° to -20° C., which is cooled to a temperature of -70° C., to which are added 0.17 g of triethylamine, a solution of 0.229 g of (3R,4R)-3-amino-4-methylsulfonyl-2-oxoazetidine in 3 ml of DMA, and 2 ml of propylene oxide, successively. The temperature of the mixture is raised up to room temperature in the course of 1.5 hours. The reaction mixture is concentrated under reduced pressure, and the residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.415 g of (3R,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylsulfonyl-2-oxoazetidine. This is in agreement with the compound (syn-isomer) obtained in Reference Example 15B in IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH3:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:55]([C:52]1[CH:51]=[CH:50][C:49]([O:48][CH3:47])=[CH:54][CH:53]=1)(=[O:57])=[O:56])[CH:5]2[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ccccc2c2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(Cl)cc3C2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A stirred solution of 8-chloro-6-methylphenanthridine (1.6 g, 7.03 mmol) in tetrahydrofuran (67 mL) was treated with sodium borohydride (2.13 g, 56.2 mmol) and trifluoroacetic acid (1.08 mL, 3.51 mmol) and heated at reflux for 5.5 hours. After cooling to room temperature, the reaction was quenched with a mixture of a saturated, aqueous, sodium bicarbonate solution and a saturated, aqueous, sodium chloride solution. The aqueous phase was extracted with diethyl ether (3×). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a crude dihydrophenanthridine. A solution of the dihydrophenanthridine in dichloromethane (19 mL) was treated with triethylamine (3.9 mL, 28.1 mmol) and 4-methoxybenzenesulfonyl chloride (1.60 g, 7.73 mmol). After stirring for 18 hours under argon at room temperature, the reaction mixture was quenched with a 1 N aqueous sodium hydroxide solution, and extracted with dichloromethane (2×). The combined organic phase was washed with a 2 N hydrochloric acid solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo to an orange solid. The orange solid was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:8) to yield the title compound (1.65 g, 4.11 mmol, 59%) as a white solid;
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16].F[B-](F)(F)F.[H+].[CH3:26][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH3:26])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(Br)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 106.1 %

Procedure:
6-Bromo-7-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-108) (912.6 mg, 2.79 mmol) and (514 mg, 1.57 mmol) were separately dissolved in methylene chloride (9 ml and 5 ml), and aqueous 42% tetrafluoroboric acid solution (420 μl, 2.79 mmol) and (240 μl, 1.57 mmol) were individually added to each, then with cooling with ice, trimethylsilyldiazomethane (2 M hexane solution, 2.8 ml, 5.58 mmol) and (1.6 ml, 3.14 mmol) were dropwise added, followed by stirring at 0° C. for 40 minutes; but since the reaction did not finish, the same amount of aqueous 42% tetrafluoroboric acid solution and trimethylsilyldiazomethane were added, followed by stirring for 19 hours with heating up to room temperature. After the reaction, the two reaction solutions were combined, water was added, followed by extraction with ethyl acetate and washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (10:1, v/v) to obtain the entitled compound (1.01 g, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:9]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccccc2Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
305 mg (1.00 mmol) of the compound from Example 110A were dissolved in 6 ml of THF, and 0.5 ml (0.50 mmol) of a 1 M solution of lithium aluminum hydride in THF was added at −10° C. The reaction mixture was then stirred at RT for 1 h. For work-up, 3 ml of saturated aqueous sodium potassium tartrate solution were added at RT, and the mixture was extracted with 15 ml of ethyl acetate. The organic phase was washed once with 10 ml of saturated sodium potassium tartrate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically [Method 19]. This gave 189 mg (68% of theory) of the target compound.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:40][O:41][C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][O:41][C:42]([NH:44][C@H:45]([C:49]([N:2]1[CH:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:1]1)=[O:50])[CH:46]([CH3:47])[CH3:48])=[O:43]
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
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: CCOC(=O)C1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (101) (200 mg, 0.94 mmol), HATU (392 mg, 1.03 mmol) and N-[(methyloxy)carbonyl]-L-valine (181 mg, 1.03 mmol) in anhydrous CH2Cl2 (6 mL) was added Hunig's base (0.33 mL, 1.88 mmol) and the solution stirred at rt under nitrogen. After 2 h, the reaction was concentrated in vacuo, purified by C18 RP chromatography, eluting with 10-90% ACN/water/0.2% NH4OH, to afford the product as a yellow oil (313 mg, 90% yield).
Reaction SMILES: [C:1]([C:5]1[NH:6][CH2:7][CH:8]([OH:11])[CH2:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:11][CH:8]([CH2:7][NH2:6])[CH2:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=NCC(O)CN1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=NCC(CN)O1
Temperature: 25 °C
Yield: 459.5 %

Procedure:
Solid 2-t-butyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine (2.55 g, 1.63 mmol) was heated to reflux in 100 mL of toluene for 22 hours. The solution was cooled to 25° C. and the slurry was filtered to remove 0.91 g of unconverted tetrahydropyrimidine after drying. The toluene filtrate was evaporated to give 1.17 g of 2-t-butyl-5-(aminomethyl)oxazoline as an oil: 1H NMR (CDCl3) δ 4.5 (m, 1H), 3.8 (apparent dd, 1H), 3.5 (apparent dd, 1H), 2.8 (apparent dq, 2H), 1.2 ppm (s, 9H), 13C NMR {1H} (CDCl3) δ 173.3 (1 C), 80.1 (1 C), 56.4 (1 C), 45.3 (1 C), 32.5 (1 C), 27.1 ppm (3 C). The neat oil gradually solidifies over a number of days, even at 0° C., reverting back to the tetrahydropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[NH2:23]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: COc1cc2nccc(O)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC

Procedure:
N1 was prepared from 6,7-dimethoxyquinolin-4-ol and 2-chloro-1-fluoro-4-nitrobenzene following the general procedure reported in Preparative Example 1 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.92 (s, 6H), 5.45 (br s, 2H), 6.28 (d, J=5.3 Hz, 1H), 6.61 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.42 (d, J=5.3 Hz, 1H). MS (ES) C17H16ClN2O3 requires: 330. Found: 331 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:30][C:31]2[CH:39]=[C:38]([CH3:40])[C:37]3[C:33](=[CH:34][N:35](COCC[Si](C)(C)C)[N:36]=3)[CH:32]=2)[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)=[O:12])[CH:4]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:30][C:31]2[CH:32]=[C:33]3[C:37](=[C:38]([CH3:40])[CH:39]=2)[NH:36][N:35]=[CH:34]3)[CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:17][CH2:18]2)=[O:12])[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1ccnc(C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)Cc2cc(C)c3[nH]ncc3c2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To the solution of (±)-3-(1-(3-(4-ethylpyridin-2-yl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (69 mg, 0.103 mmol) in tetrahydrofuran (2 mL) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (0.21 mL, 0.207 mmol, 2 equiv). The mixture was stirred at 60° C. under nitrogen for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (10% methanol in methylene chloride) to afford the desired product (50.3 mg, 91%) as a white powder: MS (ESI) [M+H]+=537. 1H-NMR (400 MHz, CDCl3) δ 8.48-8.42 (m, 1H), 7.95-7.91 (m, 2H), 7.22-7.10 (m, 2H), 7.06-6.60 (m, 6H), 4.70-4.64 (m, 1H), 4.60-4.42 (m, 1H), 4.24-3.90 (m, 3H), 3.78-3.60 (m, 1H), 3.26-2.92 (m, 3H), 2.92-2.38 (m, 8H), 1.78-1.50 (m, 3H), 1.50-1.12 (m, 2H), 1.12-0.94 (m, 3H).
Reaction SMILES: [OH-].[Ca+2].[OH-].[NH2:4][C@H:5]([C:9]([OH:11])=[O:10])[C@@H:6]([CH3:8])[OH:7].N[C@H]([C:16]([OH:18])=[O:17])CO.[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]([OH:24])=[O:23]>O>[NH2:4][C@H:5]([C:9]([OH:11])=[O:10])[CH2:6][CH2:8][C:16](=[O:17])[OH:18].[NH2:4][C@H:5]([C:9]([OH:11])=[O:10])[C@@H:6]([CH3:8])[OH:7].[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22](=[O:23])[OH:24]
Reactant: N[C@@H](CO)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: [Ca+2]
Solvent: O
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 0.33 h

Procedure:
4.2482 g of glutamine acid were dissolved in 200 mL of water by stirring after which, 2.1407 g of calcium hydroxide were added and the solution further stirred for about 20 minutes until the pH of reaction solution was about 10.44. 3.4476 g of threonine were then added and the reaction solution stirred for another 30 minutes during which time the solution pH of solution dropped to and stabilized at 9.08. Next, 3.0383 g of serine were added and the reaction solution stirred for 20 minutes after which time it was determined that the pH of the reaction solution dropped to 8.72. Finally, 3.4630 g of aspartic acid were added to the reaction solution which was then stirred for a further 190 minutes. The pH of the final clear reaction solution was pH 7.00. The final reaction solution was filtered, then evaporated in the rotary evaporator after which, the amino acid chelate product was dried to solids under vacuum as previously described. This method produced a pure amino acid chelate with a metal to amino acid ratio of about 1:4 (Ca:Glu:Thr:Ser:Asp).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+].Cl>C1COCC1>[CH:1]1([C:11]2([OH:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][CH2:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CC2)c2ccccc2CCc2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry THF (prepared from cyclopropylbromide (12.1 g, 0.10 mol), magnesium turnings (2.45 g, 0.10 mol) and dry THF (65 ml)) was placed under an atmosphere of nitrogen. A solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (10.4 g, 0.05 mol) in dry THF (25 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (50 ml) was carefully added. The mixture was neutralized with 2N hydrochloric acid and extracted with diethyl ether (2×200 ml). The combined organic extracts were dried (Na2SO4) and the solvent was evaporated in vacuo to give 13.1 g of crude 5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH2:37][N:38]4C(=O)C5C(=CC=CC=5)C4=O)(=[O:35])=[O:34])[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:38][CH2:37][CH2:36][S:33]([N:30]1[CH2:29][CH2:28][CH:27]([C:24]2[N:23]=[C:22]([NH:21][C:9]3[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][C:12]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][N:10]=3)[S:26][N:25]=2)[CH2:32][CH2:31]1)(=[O:35])=[O:34]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCS(=O)(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
2-(2-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-ylsulfonyl)ethyl)isoindoline-1,3-dione (0.110 g, 0.157 mmol) and hydrazine monohydrate (0.0236 g, 0.472 mmol) were dissolved in EtOH (25 mL) and heated to reflux for 8 hours. The reaction was cooled to ambient temperature and the solids filtered and triturated with EtOH to afford the title compound (0.013 g, 14.5% yield). 1H NMR (d6-DMSO) δ 8.38 (d, 1H), 8.36 (m, 1H), 7.66 (dt, 1H), 7.45 (d, 1H), 7.41 (t, 2H), 7.20-7.10 (m, 5H), 3.61 (d, 2H), 3.12 (t, 2H), 3.01-2.89 (m, 5H), 2.09 (d, 2H), 1.79 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:40])[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:17][C:16]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:8]2)=[O:4]>CO.[OH-].[Na+]>[CH2:33]([O:32][C:16]1[CH:17]=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]([CH:21]([CH3:23])[CH3:22])=[CH:20][C:15]=1[C:14]([N:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH2:10]1)=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OCc3ccccc3)cc1OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(C(=O)N2Cc3ccc(C(=O)O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 67.1 %

Procedure:
A solution of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (390 mg) in methanol (10 ml) and 2M NaOH (10 ml) was heated at 50° C. for 48 hours then evaporated. The residue was acidified with 2M HCl, the solid collected by filtration, washed with water and sucked dry to give 255 mg of 2-(2,4-bis-benzyloxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid as a white solid. [M+H]+ 520.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[CH3:16].[OH-].[Li+].CO.Cl>O>[CH3:13][C:12]([CH3:15])([CH3:14])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([CH3:16])[CH:6]=1
Reactant: COC(=O)c1ccc(/C=C/C(C)(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(/C=C/C(C)(C)C)ccc1C(=O)O

Procedure:
A solution of (E)-4-(3,3-dimethylbut-1-enyl)-2-methylbenzoic acid methyl ester (6.5 g, 0.028 mol) and lithium hydroxide (3.4 g, 0.14 mol) in a mixture of methanol (50 mL, 1 mol) and water (150 mL) was heated to reflux for 3 hours. Most of the methanol was stripped off and the aqueous solution was carefully acidified with conc. HCl. The white precipitate was filtered, washed with water and vacuum dried. m/z=217.1 (M−1).
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:11])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A suspension of 10.2 grams (68.1 mmol) of hydrocinnamic acid, 14.4 grams (74.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 7.31 grams (74.9 mmol) of N,O-dimethylhydroxylamine hydrochloride in 250 mL of methylene chloride was cooled to 0° C. and treated with 19.1 mL (13.9 grams, 136 mmol) of triethylamine. The mixture was stirred for 16 hours with slow warming to rt and was then concentrated. The residue was taken up in 250 mL of ethyl acetate, washed with aqueous 1N hydrochloric acid solution (2×150 mL), saturated aqueous sodium hydrogencarbonate solution (2×100 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to give 13.11 grams (99%) of the title compound as an oil. Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.65; H, 8.11; N, 7.18.