Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:31][CH3:32])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21]CC1C=CC(OC)=CC=1.[Na+].[I-].O.Cl>C(#N)C>[Cl:1][C:2]1[C:3]([O:31][CH3:32])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13]1)[CH:8]=[C:7]2[OH:21]
Reactant: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Yield: 96 %

Procedure:
Compound 234a (800 mg, 1 eq.), CeCl3.7H2O (965 mg, 1.5 eq.), and NaI (258 mg, 1 eq.) in ACN (10 mL) were stirred at 85° C. for 1 hr under microwave irradiation. Water was added and the mixture was acidified with 1N HCl to pH 5. The reaction mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (MeOH/DCM) to give compound 236a as a beige solid in 96% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 4.02 (s, 3H), 7.07 (s, 1H), 7.43 (s, 1H), 7.51 (d, J=9.11 Hz, 1H), 8.11 (d, J=9.11 Hz, 1H), 8.88 (s, 1H); MS (ESI, EI+) m/z=343.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O.C(Cl)(Cl)Cl>C(O)C.O.NN>[NH2:27][CH2:26][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3.0 g of N-[[2-chloro-4-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl]methyl]phthalimide in 70 mL of ethanol, 1.0 mL of 80% hydrazine monohydrate was added and the resultant mixture was stirred while heating the mixture to reflux for 1 hour. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 100 mL of chloroform was added to the reaction mixture to filter off an insoluble substance, followed by distilling off the solvent under reduced pressure. To the resultant residue, 50 mL of chloroform was added to dissolve the residue and to filter off the resultant insoluble substance. The filtrate was washed with water (50 mL×1) and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 2.55 g of the objective substance as a yellow resinoid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH-].[K+].[Li]CCCC.[Cl:16][CH2:17][C:18](=[O:20])[CH3:19]>CCOCC.CCCCCC.C(O)(=O)C>[N:6]1[CH:7]=[CH:8][C:3]([C:18]([OH:20])([CH3:19])[CH2:17][Cl:16])=[CH:4][CH:5]=1
Reactant: CC(=O)CCl
Reactant: Brc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(O)(CCl)c1ccncc1
Reaction time: 1 h

Procedure:
A mixture of 4-bromopyridine hydrochloride (3.8 g) and potassium hydroxide (1.1 g) was stirred at room temperature in anhydrous ether (20 cm3) for 0.5 hours. The mixture was then cooled -70°, n-BuLi (12.2 cm3 of a 1.6M solution in hexane) was added, the mixture was stirred for 1 hour and chloroacetone (1.39 g) in ether (10 cm3) was added. Stirring was continued for 1 hour, acetic acid (1.2 g) was added and the mixture was partitioned between sodium carbonate solution and ether. The organic phase was dried (MgSO4) and evaporated and the residue was chromatographed on silica ("Merck" 60.9385) eluting with ethyl acetate:petrol (b.p. 60°-80°), 2:3, to give 2-(4-pyridyl)-2-hydroxypropylchloride as a waxy solid (0.6 g). This material was taken without further purification into DMF (5 cm3) and this was then added to a solution of 2-sodioisothiazolidine-1,1 -dioxide [made from isothiazolidine-1,1-dioxide (0.65 g) and sodium hydride (0.5 g of a 50% dispersion in oil) in DMF (10 cm3)] and the mixture was heated for 3 hours at 130°. Volatile material was removed in vacuo, the residue was partitioned between chloroform and water, the aqueous phase was extracted further with chloroform (2×25 cm3) and the combined extracts were dried (MgSO4) and evaporated to afford an oil. Chromatography on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:19, gave 2-[2-(4-pyridyl)-2-hydroxy]prop-1-ylisothiazolidine-1,1-dioxide as an oil (0.48 g) which was used without further purification.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)O
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cncn3)cc2)C(=O)O1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
L-Proline (1.81 g, 15.6 mmol) was added to a stirring, heterogeneous mixture of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (13.5 g, 78.0 mmol, Intermediate 45, step a) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11.2 g, 78.0 mmol) in ethanol (520 mL) at 23° C. After 1.5 hours, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (19.7 g, 78.0 mmol) was added in one portion. After 16 hours, the ethanol was removed by rotary evaporation at 35° C. to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was stirred for 10 minutes at 23° C. The mixture was filtered and the filter cake was washed with isopropanol (150 mL). The solids were collected and dried under vacuum to provide the titled compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][S:23]([C:26]1[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].C(=O)(O)[O-].[Na+:37].O1CCOCC1>[Pd].O>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][S:23]([C:26]1[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:37]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg), 10% palladium on charcoal (30 mg), sodium bicarbonate (6 mg), dioxane (3 ml) and water (1 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with water (3×3 ml) The combined filtrate is extracted with ethylacetate (3×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to give sodium 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@@:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH:17]1([N:7]2[CH2:8][C@:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC)cc3OC)ncc2N(C)C1=O
Temperature: 95 °C
Reaction time: 36 h
Yield: 26.6 %

Procedure:
A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4H) 1.93-1.98 (m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.61 (m, 3H), 3.86 (m, 3H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C24H27F2N5O4, 488. found 488.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)([C:13]2[CH:18]=[C:17]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:16]=[C:15]([F:26])[CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.ClC(OCC)=O.[N-:44]=[N+]=[N-].[Na+].CC([O-])(C)C.[K+].CC(O)(C)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)([C:13]2[CH:18]=[C:17]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:16]=[C:15]([F:26])[CH:14]=2)[NH2:44])=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: NC(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
At 0° C. to a solution of 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoic acid (1.59 g, 2.64 mmol) in acetone (30 mL) was added TEA (442 μL, 3.17 mmol) followed by ethyl chloroformate (303 μL, 3.17 mmol). The reaction mixture was stirred at 0° C. for 45 min and NaN3 (343 mg, 5.28 mmol) was added. The reaction was stirred at 0° C. for 1 h, quenched by the addition of water and the aqueous layer was extracted with toluene (3×30 mL). The combined organic layers were washed with sat. NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was diluted with toluene (10 mL) and heated at 90° C. for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in t-BuOH/THF (1:1, 20 mL) and treated with t-BuOK/t-BuOH (1 N, 13.2 mL, 13.2 mmol). The reaction mixture was stirred at rt overnight, then heated at 85° C. for 3 h. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. NaCl, dried over magnesium sulfate, filtered and concentrated. The residue was purified by ISCO (40 g siligel column, 0-40% EtOAc/hexane over 40 min to yield 2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine as a colorless oil (1.2 g, 82% yield). LCMS: RT=1.82 min [M+H] 556.8 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (1H, d, J=6.15 Hz), 7.48-7.53 (1H, m), 7.30 (1H, d, J=7.91 Hz), 7.15 (1H, t, J=9.23 Hz), 6.96-7.00 (2H, m), 6.89 (1H, d, J=8.79 Hz), 6.61 (2H, d, J=7.91 Hz), 5.89 (1H, t, J=53 Hz), 3.49 (1H, d, J=13.6 Hz), 3.43 (1H, d, J=13.6 Hz), 1.50-1.65 (2H, m).
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>O1CCOCC1>[O:14]=[C:10]1[NH:11][CH2:12][CH2:13][N:9]1[C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1
Reactant: O=C1NCCN1
Reactant: O=C1NOCC(=S)N1
Solvent: C1COCCO1
Product: O=C1N=C(N2CCNC2=O)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.8 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of dry freshly distilled dioxane is added 0.66 g (0.007 mole) of 2-imidazolidone. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 1.3 g (94 percent) of 5-(2-oxo-1-imidazolidinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:13]1[CH2:14][CH:15]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
Prepared from compound 9a and 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:28](=[O:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCNCCC1OCCO1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCC1OCCO1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To an ice-cooled solution of N-(2-(1,3-dioxolan-2-yl)ethyl)-2-((tert-butyldimethylsilyl)oxy)ethanamine (0.85 g, 3.09 mmol) and di-iso-propylethylamine (0.82 mL, 4.63 mmol) was added acetyl chloride (0.26 mL, 3.71 mmol). The reaction mixture was stirred with ice-cooling for 1 hour, then the coolant was removed and stirring continued at RT for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and the organic phase poured through a hydrophobic frit. The solvent was evaporated at reduced pressure to afford the title compound (0.64 g, 65%).
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12]/[C:13](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)/[C:14]([OH:16])=[O:15])=[O:11]>C(O)C.[Pd]>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([OH:16])=[O:15])=[O:11]
Reactant: Cc1ccc(/C=C(\CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a suspension of (E)-3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzylidene)propionic acid (250 mg) in ethanol (10 ml) was added 10% Pd-C (20 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure for 16 hours. After the catalyst was filtered off, the solvent was evaporated under reduced pressure and the residue was crystallized from diethyl ether to give 220 mg of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].[CH2:6]([N:10]=[C:11]=[N:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH3:9].O.Cl>CO>[ClH:1].[CH2:13]([NH:12][C:11]([NH:4][C:3]([NH2:5])=[NH:2])=[N:10][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN=C=NCCCC
Reactant: N=C(N)N
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCN=C(NCCCC)NC(=N)N

Procedure:
0.715 g. (7.5 mmol) of guanidine hydrochloride, 1.54 g. (10 mmol) of di-n-butyl carbodiimide, 5 ml. of water, and 15 ml. of methanol is heated for 16 hours under reflux. After evaporation, the oily residue is taken up in 15 ml. of water and extracted three times with respectively 20 ml. of ether in order to remove the 1,2-di-n-butyl urea formed as a by-product. The aqueous phase is mixed with concentrated hydrochloric acid to a pH of 4 and crystallizes during evaporation. The crude product having a melting point of 102°-105° C. is still contaminated by guanidine hydrochloride and minor amounts of 1,2-di-n-butyl urea. The product is suspended in dry chloroform, the remaining guanidine hydrochloride is filtered off, the chloroform solution is concentrated by evaporation, and the solid residue is recrystallized from acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([O:21]CC)=[O:20])=[N:4][N:5]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.[OH-].[Na+].Cl>CO>[OH:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[N:4][N:5]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12
Reactant: CCOC(=O)c1nn2c(c1O)C(=O)N(C)C[C@@H]2c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C[C@H](c2ccccc2)n2nc(C(=O)O)c(O)c2C1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (7S)-3-hydroxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (0.30 g, 1.00 mmol) in MeOH (10 mL) was added aqueous 1N NaOH (5.97 mL, 5.97 mmol). The reaction was stirred at 50° C. overnight and quenched by the addition of aqueous 3N HCl (2.00 mL, 2.00 mmol). Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a light pink solid. 1H NMR (400 MHz, d6-DMSO) δ 8.90 (bs, 1H), 7.37 (m, 3H), 7.08 (m, 2H), 5.74 (t, J=4.6 Hz, 1H), 4.15 (dd, J=13.4, 4.6 Hz, 1H), 3.86 (dd, J=13.4, 4.7 Hz, 1H), 2.89 (s, 3H); ES MS (M+1)=288.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[C:11](=O)([O:37]C1C=CC=CC=1)[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[O:37])[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:19][CH:20]=1)(=[O:9])=[O:8]
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccn1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:18])[C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:18])[C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Yield: 82.1 %

Procedure:
Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.05 g, 3.63 mmol) and lithium hydroxide (174 mg, 7.26 mmol) were combined in THF (10 mL) and water (ca. 1.5 mL) was added dropwise until a solution formed. The resultant mixture was stirred at RT for 12 h. The THF was removed in vacuo and the residue acidified using aqueous HCl (1 M). The resultant precipitate was filtered to afford 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (820 mg, 82%): m/z 273 (M−H)− (ES−).
Reaction SMILES: C[OH:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C=CC=C>O.Cl>[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:2])=[CH:19][CH:18]=1
Reactant: C=Cc1ccccc1
Reactant: CO
Agent: C=CC=C
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: C=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
483 g of the methanol solution from Ex. 5 were stripped of the solvent and the residue dissolved in 1300 ml of RO water containing 118 g of conc. hydrochloric acid to prepare a 9.9 percent aq. solution of the protonated water-soluble poly(4-vinylpyridine) RAFT macroinitiator. One gram of potassium persulfate was then dissolved in 252.5 g of the 9.9 percent aq. macroinitiator solution (˜25 g polymer). This solution was then charged into a one quart heavy-walled bottle preflushed with nitrogen, followed by the addition of 60.0 g (0.577 moles) of styrene and 90.0 g (˜1.67 moles) of butadiene. The bottle was then capped and tumbled in a 65° C. water bath. The progress of the reaction was monitored gravimetrically by periodically sampling solids content by means of a syringe needle through a gasketed hole in the metal cap. After 23 hrs., the bottle was removed from the bath and cooled to room temperature to stop polymerization. The solids content was determined to be 32.3 percent or ˜70 percent conversion of the styrene and butadiene.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[NH:2][NH2:3].[C:18](OC)(=[O:21])[NH:19][NH2:20]>CO>[NH:19]([C:18]([NH:3][NH:2][C:1]([O:5][CH:6]1[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]1)=[O:4])=[O:21])[NH2:20]
Reactant: CON1C(C)(C)CC(OC(=O)NN)CC1(C)C
Reactant: COC(=O)NN
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)NNC(=O)NN)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 28 (1 mole) with methyl carbazate (1 mole) by refluxing the reaction mixture in methanol.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15].[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C:26]1=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C:26]1([C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOc1ccc(C)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
A 1.6 M hexane solution of n-butyl lithium (11 ml) was added dropwise to a solution of 3-bromo-4-ethoxytoluene (3.6 g) in THF (50 ml) at −78° C. and the mixture was stirred for 15 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (7.6 g) in THF (10 ml) was added dropwise to the reaction mixture and the mixture was stirred for 2.5 hours. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The resulting precipitates were collected by filtration to obtain 2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose (3.53 g).