Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[H-].[Na+].[Cl:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]Cl.O>CN(C=O)C>[Cl:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:11]1=[O:19]
Reactant: ClC/C=C\CCl
Reactant: O=c1[nH]c2ccccc2n1CCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(C/C=C\CCl)c2ccccc2n1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a solution of 1-[2-(tetrahydro-2H-pyran-2yloxy)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (12 g, 46 mmoles) in DMF (120 ml) was added 80% sodium hydride (1.7 g, 55 mmoles) and the mixture was stirred at room temperature for 1 hour. Cis-1,4-dichloro-2-butene (5.8 ml, 55 mmoles) was added dropwise and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was taken to dryness and the residue was purified by flash chromatography (cyclohexane-ethyl acetate 70-30) to give 2.8 g of the title compound as a thick oil which was used without any further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][NH:5]1.[Cl:11][CH:12]([Cl:16])[C:13](Cl)=[O:14]>O.C(Cl)Cl>[Cl:11][CH:12]([Cl:16])[C:13]([N:5]1[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]1[CH3:3])=[O:14]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1NCCNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1C(=O)NCCN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
A solution of 8 g (0.2 mole) of sodium hydroxide in 15 ml of water was added to a solution of 20 g (0.18 mole) of 2-methyl-piperazin-3-one in 150 ml of methylene chloride. 26.6 g (0.18 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred at 25° C. for 10 hours and the precipitated crude product was filtered off with suction, washed with water and recrystallized from a 2:1 mixture of isopropanol and H2O to give 14.4 g (36% theory) of 1-dichloroacetyl-2-methyl-3-oxo-piperazine of melting point 167°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[N:3]=1.Br>O>[Cl:1][C:2]1[N:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2cccc(Cl)n2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(Oc2cccc(Cl)n2)cc1

Procedure:
A mixture of 11 grams of 2-chloro-6-(4-methoxyphenoxy)pyridine, prepared above in Example IX and 100 milliliters of 48 percent hydrobromic acid was heated at reflux overnight. The reaction mixture was cooled and diluted with water. The 4-((6-chloro-2-pyridyl)oxy)phenol separated out as a yellow crystalline solid which was isolated by filtration. The product was recovered in a yield of 10 grams (97 percent of theoretical) and melted at 125°-130° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:18])[CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:5]2=[N:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[Cl:18][C:8]1[CH:9]=[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:5]2[N:6]([C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccncc1-c1cc(Cl)nn2c(Br)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2c(-c3ccccc3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
A microwave vial was charged with a mixture of 3-bromo-6-chloro-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine (64 mg, 0.198 mmol), phenylboronic acid (24.12 mg, 0.198 mmol), tetrakis(triphenylphosphine)palladium(0) (22.86 mg, 0.020 mmol), dioxane (4 mL), and K3PO4 (0.297 mL, 0.593 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep. HPLC to give 38 mg (44.3%) of the product. LC/MS: Rt=2.36 min. LC/MS (Condition A): 321.09/323.10.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([C:13]([NH:15][C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28](=[O:37])[N:29]([CH3:36])[C:30](=[O:35])[N:31]([CH3:34])[C:32]=3[CH3:33])=[CH:23][CH:22]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+]=[N-].CP(C)C>>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([C:13]([NH:15][C@@H:16]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:28](=[O:37])[N:29]([CH3:36])[C:30](=[O:35])[N:31]([CH3:34])[C:32]=3[CH3:33])=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCN=[N+]=[N-])CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: CP(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCN)CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 10, starting from (S)-2-[[1-(4-azidobutyl)cyclopentanecarbonyl]amino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid (1.02 g, 2 mmol) and trimethylphosphine (8 mL, 8 mmol, 1M) to obtain a white solid (0.96 g, 99%). ES(+)-HRMS m/e calcd. for C26H36N4O5 (M+H)+ 485.2759, obsd. 485.2757.
Reaction SMILES: [CH:1]1([CH2:7][C:8](OC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC.O>[CH:1]1([CH2:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=CCC1CCCCC1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of methyl cyclohexylacetate (1.56 g, 10 mmol) in 25 mL anhydrous ether was stirred at −78° C. under argon. DIBAL (1M in hexane, 11 mL, 11 mmol) was added dropwise over 45 minutes and the reaction mixture was stirred for an additional 1 hour. A solution of potassium sodium tartrate tetrahydrate (6 g, 12.2 mmol) in 25 mL water was added and the mixture stirred at room temperature overnight. After dilution with ether, the organic layer was washed with 0.5 N HCl, saturated sodium bicarbonate and saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to give cyclohexyl-acetaldehyde (1.17 g, 93%).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([CH:22]=1)[CH2:10][N:11]([CH3:21])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([CH:22]=1)[CH2:10][N:11]([CH3:21])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Reactant: NO
Solvent: CCO
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydroxylamine (50% in water) (513.54 μL; 8.55 mmol; 5 eq.) was added to a solution of tert-butyl N-(5-cyano-2-fluorobenzyl)-N-methyl-beta-alaninate, obtained in step 1 (500 mg; 1.71 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at RT for 24 hours. Solvent was evaporated in vacuo and the resulting oily residue was freeze-dried to afford the title compound as a colourless oil (560 mg; quantitative). 1H NMR (CDCl3) δ 7.74 (dd, J=6.6, 2.2 Hz, 1H), 7.58-7.53 (m, 1H), 7.03 (t, J=9.1 Hz, 1H), 5.10 (s, 2H), 3.59 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.44 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.46 (s, 9H). LC/MS (Method B): 326.2 (M+H)+. HPLC (Method A) Rt 2.18 min (Purity: 86.2%).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([S:6][C:7]1[C:8]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>O.CN(C=O)C.CC(C)=O>[CH2:1]([N:15]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=1)[C:13](=[O:14])[C:8]1[C:7]([S:6][CH2:4][CH3:5])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2]
Reactant: CCI
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)N(CC)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
0.78 g of ethyl iodide was added to a mixture of 0.32 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 2), 0.21 g of potassium carbonate and 3 mL of acetone, and the mixture was stirred at room temperature for 1 hour. 3 mL of DMF was added to the reaction mixture, the mixture was stirred at 60° C. for 1 hour and then cooled to room temperature, and 1.0 g of ethyl iodide was added and then the mixture was stirred at 60° C. for 2 hours. Water and a saturated aqueous sodium bicarbonate solution were poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.17 g of N-ethyl-3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 26).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[C:12]1([C@H:18]([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])[CH:27]=O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+]>CN(C)C=O.C(OCC)(=O)C.CO>[C:12]1([C@H:18]([O:23][C:24]2[CH:25]=[C:26]([CH:27]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][C@H:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](COc1ccc(C=O)cc1O[C@@H](c1ccccc1)C(F)(F)F)c1ccccc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](COc1ccc(C=C2SC(=S)N(CC(=O)O)C2=O)cc1O[C@@H](c1ccccc1)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
A solution of rhodanine-3-acetic acid (461 mg, 2.41 mmol, 1 eq), 3-[(S)-1-phenyl-2,2,2-trifluoroethoxy]-4-[(S)-2-phenylpropoxy]benzaldehyde (1.0 g, 2.41 mmol, 1 eq) and ammonium acetate (558 mg, 7.24 mmol, 3 eq) in N,N-dimethylformamide (10 mL) was heated to 90° C. and stirred for 15 min. It was then cooled to room temperature and diluted with ethyl acetate (100 mL). The organic solution was washed with 1M HCl (2×200 mL), and brine (200 mL), then dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel; elution with ethyl acetate followed by ethyl acetate:methanol (9:1) gave a yellow gum which was dissolved in methanol (5 mL) and added dropwise to stirred ice-cold water (100 mL). A fine suspension was obtained, which was freeze-dried over 3 days to give the product as a yellow powder (1.04 g, 73%) mp 73–80° C.: 1H NMR (d6 DMSO) δ 7.64 (s, 1H, C═C—H), 6.04 (q, 1H, J 6.4 Hz, CHCF3), 4.61 (s, 2H, CH2CO2H), 4.22 (m, 2H, OCH2CHCH3Ph), 3.26 (m, 1H, OCH2CHCH3Ph), 1.38 (d, 3H, J 7.2 Hz, OCH2CHCH3Ph) 19F NMR (d6 DMSO) −75.80. Anal. Found: C, 59.31; H, 4.42; N, 2.36; Calcd for C29H24F3NO5S2: C, 59.27; H, 4.12; N, 2.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 80 °C
Yield: 69.9 %

Procedure:
2.33 g of 5-bromopyridin-2-ylamine and 3.14 g of 2-bromo-1-(4-chlorophenyl)-ethanone are placed in 110 ml of n-propanol in a round-bottomed flask. 1.58 g of sodium hydrogencarbonate are added. The mixture is heated at 80° C. for 16 h and allowed to cool to ambient temperature. 400 ml of water are added. The precipitate is collected by filtration, washed with water and dried in an oven under reduced pressure. 2.89 g of compound are obtained. 1H NMR spectrum (d6-DMSO, δ in ppm): 7.4 (d, 1H); 7.5 (d, 2H); 7.6 (d, 1H); 8.0 (d, 2H); 8.4 (s, 1H); 8.9 (s, 1H). M+H=308.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 40 °C

Procedure:
A mixture of 22-3 (700 mg, 2.2 mmol), 1N NaOH, and ethanol (10 mL) was heated at 40° C. for 4 hours. The cooled reaction mixture was acidified with 10% KHSO4 and then extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4) and concentrated to give 22-4 as a white solid. TLC Rf =0.80 (silica, 10:0.5:0.5 CH2Cl2 /CH3OH/AcOH);
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1C(=O)N([Cl:18])C(=O)C1.OS([O-])=O.[Na+]>CC#N>[Cl:18][C:6]1[C:7]([OH:10])=[CH:8][CH:9]=[C:2]([OH:1])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1c(O)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
2,5-dihydroxy-benzaldehyde (100 g, 0.725 mol) was dissolved in MeCN (1L). To the solution was added NCS(N-chlorosuccinimide, 106 g, 1.1 eq) in batches under N2 protection. After addition completed, the mixture was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, NaHSO3(38%, 500 mL) was added to the mixture, then extracted with ethyl acetate (3×600 mL) The organic layer was washed with water (2×600 mL) and brine (600 mL), dried over anhydrous MgSO4, concentrated to give a crude product, which was recrystallized to give the desired product 7A (25.6 g, 20.5% yield), as a yellow solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:25])[S:8][C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)[N:6]2[C@H:5]1[C:22]([OH:24])=[O:23]>O>[NH2:6][C@H:5]([C:22]([OH:24])=[O:23])[C:4]([SH:8])([CH3:25])[CH3:3]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(S)[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
N-(2-aminoethyl) carbamylmethylated cellulose was prepared in the manner set forth in Example 1. The amino ethyl derivative was kept at a concentration of 6.5 mg/ml in aqueous solution. Three ml of this solution were diluted to 6 ml with distilled water. The pH was adjusted to 9 with 0.1 N NaOH. One hundred mg of Penicillin G (sodium salt, Sigma Chemicals, St. Louis, U.S.A.) were added at once, and the resulting solution left overnight at room temperature. The solution was then dialyzed in the cold against two daily changes of 2 liters of water for 3 days. The CMC-Pen conjugate thus formed was kept in solution in the cold.
Reaction SMILES: OO.[C:3]1([N:9]2[C:14](=[O:15])[C:13]([Cl:16])=[C:12]([S:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=[O:26])C>O>[C:3]1([N:9]2[C:14](=[O:15])[C:13]([Cl:16])=[C:12]([S:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:26])[CH:11]=[N:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: O=c1c(Cl)c(SC2CCCCC2)cnn1-c1ccccc1
Agent: OO
Solvent: O
Product: O=c1c(Cl)c(S(=O)C2CCCCC2)cnn1-c1ccccc1
Reaction time: 12 h

Procedure:
5.1 parts by volume of 30% strength by weight hydrogen peroxide were added dropwise to a solution of 16 parts by weight of 1-phenyl-4-(cyclohexylthio)-5-chloropyridazin-6-one in 100 parts by volume of glacial acetic acid, and stirring was continued for 12 hours at 60° C. The reaction mixture was then stirred into 1,000 parts by volume of water, and the precipitate was filtered off under suction, washed with water and dried under reduced pressure. 16.3 parts by weight of 1-phenyl-4-(cyclohexyl-sulfinyl)-5-chloropyridazin-6-one of melting point 128°-130° C. were obtained (compound No.1).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1Cc1ccccc1

Procedure:
3.170 ml of toluene and 10.5 g of bleaching earth (Tonsil K 10 from Sudchemie AG) were heated to boiling in a stirring vessel with a distillation passage, condenser and water separator. 216 g of benzyl alcohol were then passed in through a jet in the course of about 2 hours, i.e. benzyl alcohol was added dropwise under a flow of nitrogen (100 1/h) via an immersed thin tube and in this way was rapidly and uniformly distributed and made to react.
Reaction SMILES: [CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.C[O:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH2:27][CH2:28][CH3:29].ClC(Cl)Cl>P([O-])([O-])([O-])=O>[CH2:1]1[CH2:21][N:20]2[C:4]3[C:5]([CH2:17][CH2:18][CH2:19]2)=[C:6]2[O:13][C:11](=[O:12])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][C:7]2=[CH:8][C:3]=3[CH2:2]1.[NH2:30][CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:24]([OH:31])=[O:23]
Reactant: CCCCC(N)C(=O)OC
Agent: O=C(O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCCCC(N)C(=O)O

Procedure:
Coumarin 343-aminohexanoic acid-methyl ester (0.1 mmol) was dissolved in 200 ml phosphate buffer (10 mM, pH 7.0) and 20 mg esterase was added (EC 3.1.1.1.; Sigma No: E-3019). After stirring for three days at ambient conditions (room temperature) the methyl ester has been cleaved quantitatively. The product was isolated by extraction of the aqueous phase with trichloromethane. The separated organic phase was washed with H2O and brine (H2O saturated with NaCI). After drying over magnesium sulfate and removal of the solvent in a vacuum on a rotary evaporator, the residuum is dissolved in dioxane and lyophilized.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cncc(F)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Yield: 55.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-amine (423 mg, 2.1 mmol), described in the previous step, and potassium carbonate (290 mg, 2.1 mmol) in anhydrous DCM (3.4 ml) was added dropwise phenyl chloroformate (0.61 ml, 4.8 mmol) as a solution in DCM (2 ml) to afford phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (411 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 1.28 (s, 9H), 6.47 (s, 1H), 6.95-7.41 (m, 7H), 7.72-7.82 (m, 1H), 8.40 (d, J=8 Hz, 1H); LC-MS (ESI) m/z 355 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[N:3]=1.[Sn](Cl)Cl>C(O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:4]2[N:3]=[C:2]([Cl:1])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1c(Cl)nc(SCc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)Cc1c(Cl)nc(SCc2ccc(N)cc2)nc1N(C)C
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a suspension of 2 (1.11 g) in ethanol (25 mL0 at room temperature was added tin(II) chloride dehydrate (3.81 g) and the resulting mixture was refluxed for 2 hours. After cooling to rt, the volume was reduce by approximately half by concentration in vacuo and the remaining clear yellow solution was poured into chilled saturated sodium bicarbonate solution. The resulting white suspension was treated with EtOAc and filtered through Celite. The filtrate was allowed to separate and the aqueous layer was extracted with EtOAc thrice. The combined organic extracts was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give crude 3 as an orange oil (1.12 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:21][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:37][CH:38]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)C(O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)OCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
A solution of methyl 3-(4-tert-butyldimethylsilyloxyphenyl)-2-hydroxypropionate (300 mg, 0.97 mmol) in THF (2 ml) at −78° C. was treated with a suspension of sodium hydride (60%, 40 mg, 1 mmol) in THF (1 ml). The mixture was stirred at −40° C. for 15 minutes, then tetrabutyl ammonium iodide (20 mg) and tert-butyl 4-bromomethylbenzoate (270 mg, 0.97mmol) dissolved in THF (1 ml) were added. After the cooling bath was removed, the mixture was stirred for 16 hours, quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (hexane:ethyl acetate=85:15) to give the title material (200 mg, 41%) as a colorless oil.