Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(S([C:39]1[CH:40]=[CH:41][C:42](OC)=[C:43]([NH2:45])[CH:44]=1)(=O)=O)C>>[CH2:2]1[C:39]2[C:40](=[CH:41][CH:42]=[C:43]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and [5-(ethylsulfonyl)-2-(methyloxy)phenyl]amine: MS (APCI): 641 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[Cl:13][C:14]1[S:18][N:17]=[C:16]([OH:19])[CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[S:18][N:17]([CH2:3][CH2:2][C:1]([C:5]2[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=2)=[O:4])[C:16](=[O:19])[CH:15]=1
Reactant: Oc1cc(Cl)sn1
Reactant: C=CC(=O)C1=CC(=O)C=CC1=O
Solvent: Cc1ccccc1
Product: O=C1C=CC(=O)C(C(=O)CCn2sc(Cl)cc2=O)=C1

Procedure:
A stirred solution of 2-acryloyl-1,4-benzoquinone (1.0 g, 0.007 mole) and 5-chloro-3-hydroxyisothiazole (0.81 g, 0.006 mole) in 20 ml of toluene was heated at 80° C. for 4 hours. Upon cooling, the precipitate which formed during the reaction period was removed by filtration and recrystallized from ethyl acetate/acetone mixture. A gray/tan solid was obtained; 0.85 g; mp 181°-183° C.; IR (KBR) 1635 cm-1 (broad);NMR (acetone-d6) δ7.35 (s,1H); 7.15 (d 1H); 6.85 (d 1H); 6.35 (s,1H); 4.2 (t,2H); 3.52 (t,2H).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(N)ccc2O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(NC(C)=O)ccc2O1
Reaction time: 0.5 h

Procedure:
The ethyl 2-(6-aminochroman-2-yl)acetate toluene solution of Example 4 (6 L) was cooled to −5° C. in a sodium chloride-ice bath, and 293 g of anhydrous pyridine added in a single portion. To the well-stirred mixture was added dropwise 246 g of acetyl chloride, maintaining the temperature between −5° C. and 5° C. The reaction was not complete by TLC after 30 min, so an additional 50 g of anhydrous pyridine and 50 g of acetyl chloride were added dropwise, and the reaction stirred for 30 min. The reaction was quenched with 4 L of water, stirred for 15 minutes, and the organic fraction was separated. The aqueous fraction was extracted with 2×500 mL of toluene, and the combined toluene fractions washed with 2 L of water. Complete removal of toluene afforded ethyl 2-(6-acetamidochroman-2-yl)acetate as a dark brown residue, which was transferred into a 12-L flask.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.Cl.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:27])[C:25]=1Cl.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:27])[C:25]=1[N:15]1[CH2:16][CH2:17][CH:12]([C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[O:11])[CH2:13][CH2:14]1
Reactant: Fc1cncc(Br)c1Cl
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3Br)CC2)CC1
Temperature: 150 °C

Procedure:
A mixture of (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (50.65 g, 178.2 mmol), 3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (40 g, 162 mmol) and dipotassium carbonate (94.04 g, 680.4 mmol) in NMP (400 mL) was heated at 150° C. overnight. The mixture was cooled to room temperature then filtered to remove inorganic salts and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (800 mL), washed with brine (100 mL×4), dried (MgSO4), filtered and concentrated in vacuo to afford a brown viscous oil. This residue was purified by silica gel column (approx 800 g of silica), product loaded onto silica in DCM, then eluting with 3% methanol (containing 10% ammonium hydroxide)/DCM to afford the desired product as a brown oil which crystallised on standing (27.44 g, 44%). MS (ES+) 387.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](ON3C(=O)CCC3=O)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(CN)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of 3-amino-2,2-dimethylpropanoic acid hydrochloride (1.0 g, 6.5 mmol, 1.0 eq.) in 10 mL of 10% Na2CO3 was added to a solution of 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dione (2.3 g, 6.5 mmol, 1.0 eq.) in 10 mL of DME. The reaction was allowed to stir at room temperature overnight. Reaction was concentrated to a smaller volume and then washed two times with ether. The aqueous layer was acidified to pH<2 with concentrated HCl and then extracted three times with a 10% methanol 90% dichloromethane solution. The organics where combined before being washed with 1M HCl and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo producing #124 (2.2 g, 98%) as a white solid. LC-MS (Protocol Q1): m/z 362.0 [M+Na+] retention time=0.89 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:10]([CH3:28])[CH:9]=2)[CH:5]=[C:4]([CH3:29])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:10]([CH3:28])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(CN3CCNCC3)c(C)c2)cc(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.9 %

Procedure:
A 50 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate (350 mg, 0.880 mmol, 1.00 equiv) and dichloromethane (5 mL). Trifluoroacetic acid (0.5 mL) was added dropwise at 0° C. The resulting solution was stirred for 5 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 270 mg (crude) of 1-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:11]([C:14]1[O:18][C:17]([C:19](Cl)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[O:18][C:17]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: N=C(NO)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nc(-c3ccccc3)no2)o1
Temperature: 25 °C

Procedure:
N-Hydroxy-benzamidine (0.3 g; 2.1 mmol) was dissolved in 10 ml of dry pyridine and added 0.5 g of 5-nitro-furan-2-carbonyl chloride (2.8 mmol). The reaction mixture was heated at reflux for 3 hours, cooled to room temperature and poured into 50 ml of ice/water, the product precipitated out of solution and was isolated by filtration. Yield 0.3 g (41%) of yellow solid. Mp. 164-166° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][OH:17])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[OH:17])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OCc1ccccc1/C(=N\O)C(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.6 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (388 mg, E/Z=35/65) was dissolved in a 5N hydrogen chloride/dioxane solution (3.3 ml), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate three times. The combined ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (300 mg). This crude product was crystallized from ethyl acetate-hexane, and the crystallization mother liquor was concentrated under reduced pressure and purified by silica gel thin layer chromatography (ethyl acetate:hexane=4:1) to obtain the title compound (243 mg in total, yield: 62.8%, pale yellow crystals).
Reaction SMILES: Br[CH:2]([F:28])[C:3]([F:27])([F:26])[S:4][C:5]1[NH:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:26][C:3]1([F:27])[S:4][C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:9]2[CH:2]1[F:28]
Reactant: COc1ccc(-c2nc(SC(F)(F)C(F)Br)[nH]c2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)C(F)C(F)(F)S3)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 89.2 %

Procedure:
A mixture of 0.95 g (2 mmoles) of 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5-bis(p-methoxyphenyl) imidazole, 0.6 g (4 mmoles) potassium carbonate and 10 ml dimethylformamide was stirred at 50°-60° for 2 days. The mixture was poured into ice water. The aqueous mixture was extracted three times with ether. The ether was backwashed three times with water, then dried and concentrated on a rotary evaporator. The residue, 0.5 g of crystals, was combined with 0.3 g of product with precipitated from the aqueous layers on standing. The combined crude product was recrystallized from methyl cyclohexane to give 0.7 g of pure product, m.p. 160°-2°. IR: 3.32μ, =CH; 3.50μ, sat. CH; 6.15, 6.54, 6.61μC=C and C=N; strong 8.02μ, aryl C--O; 9.67μ, C--F.H--NMR: 3.8, 3.85δ (2 singlets, 6H); two doublets 5.6, 6.4δ (JHF1 ~61 cps; JHF1 ~7 cps; JHF3 ~0-1 cps, 1H); 2 overlapping A2B2 quartets 6.7-7.6δ (8H). F--NMR: F2 : two doublets, 75.09 and 72.82δ; F3 : two doublets, 86.88 and 89.16δ; F1 : two doublets centered at 139.78δ (JHF1 ~61 cps; JHF2 ~7 cps; JHF3 ~1 cps; JF1F2 ~4 cps; JF1F3 ~8.5 cps; JF2F3 ~213 cps).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH2:8][S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH2:25]([OH:28])[CH2:26][OH:27].C1COCC1>CC(C)([O-])C.[K+]>[C:12]1([S:9]([CH2:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[N+:22]([O-:24])=[O:23])[O:27][CH2:26][CH2:25][OH:28])(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene (14.6 g, 42.3 mmol) and ethylene glycol (35 mL, 630 mmol) in 1.0 N potassium tert-butoxide in THF (90 mL, 90 mmol) was refluxed under nitrogen for one hour. After cooling to ambient temperature, the reaction mixture was concentrated. Excess water was added to the residue, and the mixture was poured into ice/2N hydrochloric acid. It was extracted with ethyl acetate and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 80° C. for 25 minutes to yield 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethanol as a brown gum (14.3 g, 87.2%). Mass Spectrum (−EI, [M−H]−) m/z 386. 1HNMR (500 MHz, DMSO-d6): δ8.56-8.57 (m, 1H), 8.35 (d, 1H, J=8.24 Hz), 8.14-8.15 (m, 1H), 8.00-8.02 (m, 2H), 7.65-7.75 (m, 3H), 7.11-7.13 (m, 1H), 6.89 (d, 1H, J=2.90 Hz), 5.27 (s, 2H), 4.92 (t, 1H, J=5.49 Hz), 3.93-3.95 (m, 2H), 3.67 ppm (dd, 2H, J=9.91 Hz and 5.34 Hz). Elemental Analysis for C19H17NO6S.0.25 mol H2O: Calcd: C, 58.23; H, 4.50; N, 3.57; Found: C, 57.83; H, 4.25; N, 3.50.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL of 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CO)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-serine methyl ester, hydrochloride (15.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-serine methyl ester (22.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([PH:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])([CH3:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:8]([P:12](=[O:17])([C:13]([CH3:16])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)[PH](=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)P(=O)(c1ccccc1)C(C)(C)C

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 186 mg (0.20 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 1.57 g (10.0 mmol) of bromobenzene, 1.62 g (10.0 mmol) of di-tert-butylphosphine oxide and 1.38 g (10.0 mmol) of K2CO3 in 20.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 23 h to afford di-tert-butylphenylphosphine oxide. 31P NMR (CDCl3, 121 MHz): δ51.9 ppm.
Reaction SMILES: [CH:1](/[CH:5]1[CH2:10][O:9][CH:8](CCCCC(CO)CO)[O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].FC1C=C(C=CC=1F)C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](/[CH:5]1[CH2:10][O:9][CH2:8][O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4]
Reactant: CC/C=C/C1COC(CCCCC(CO)CO)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(F)c(F)c1
Solvent: O
Solvent: c1ccccc1
Product: CC/C=C/C1COCOC1

Procedure:
A solution of 1.72 g of (E)-2-[4-(5-but-1-enyl-1,3-dioxan-2-yl)butyl]-1,3-propanediol and 1.0 g of 3,4-difluorobenzaldehyde in 30 ml of benzene is heated to slight boiling with 35 mg of p-toluenesulfonic acid monohydrate for 1 hour. After neutralization of the solution with a few drops of triethylamine the mixture is washed with water, dried over sodium sulfate, filtered and the filtrate is evaporated. The crude product is chromatographed on 40 g of silica gel with hexane/ethyl acetate 5% (v/v). Two-fold crystallization of the resulting isomer mixture from hexane yields pure (E)-trans-2-(3,4-difluorophenyl)-5-[4-(trans-5-but-1-enyl-1,3-dioxane.
Reaction SMILES: [O:1]1[CH2:4][C:2]1([C:5]([F:8])([F:7])[F:6])[CH3:3].[C:9]([CH2:12][N:13]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:15][CH2:14]1)([OH:11])=[O:10].[OH-].[K+]>O1CCOCC1.O>[OH:1][C:2]([C:5]([F:8])([F:7])[F:6])([CH3:3])[CH2:4][N:22]1[CH2:23][CH2:24][N:13]([CH2:12][C:9]([OH:11])=[O:10])[CH2:14][CH2:15][N:16]([CH2:29][C:30]([OH:32])=[O:31])[CH2:17][CH2:18][N:19]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:21]1
Reactant: CC1(C(F)(F)F)CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1)C(F)(F)F
Temperature: 70 °C
Reaction time: 24 h

Procedure:
10.29 g (86.58 mmol) of 2,3-epoxy-2-trifluoromethylpropane and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. (with exclusion of pressure). It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 11.04 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.CC1N(CC(N2CCC(C3SC=C(C4C=C(C5C=CC=CC=5)ON=4)N=3)CC2)=O)N=C(C(F)(F)F)C=1.[CH3:62][NH:63][CH:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:65][NH2:66].C(=O)([O-])[O-].[K+].[K+].II>C(O)(C)(C)C>[CH3:62][N:63]1[CH:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:65][N:66]=[C:1]1[C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CNC(CN)c1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1
Agent: II
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NCC(c4ccccc4)N3C)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step B) (0.8 g, 2.07 mmol) in tert-butanol (5 mL) was added N1-methyl-1-phenyl-1,2-ethanediamine (43.57 mg, 0.29 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes, and then potassium carbonate (107.8 mg, 0.78 mmol) and iodine (43.57 mg, 0.33 mmol) were added. The reaction mixture was stirred at 70° C. for 3 h and then quenched by addition of saturated aqueous sodium sulfite solution until the iodine color almost disappeared. The reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative thin-layer chromatography on silica gel using a mixture of 94% ethyl acetate, 5% methanol and 1% triethylamine as eluant to give 64 mg of the title product as an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:20]OS(C)(=O)=O)(=[O:4])=[O:3].[Na+].[I-].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][CH2:20][C@@H:6]1[CH2:7][C@@H:8]([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](COS(C)(=O)=O)N(S(C)(=O)=O)C2)cc1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: COc1ccc(CS[C@@H]2C[C@@H](CNCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Yield: 65 %

Procedure:
A slurry of 300 mg (0.73 mmol) (2S,4R)-methanesulfonic acid 1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl ester and 109 mg (0.73 mmol) of NaI in 5 ml benzylamine was heated in the oil bath to 100° C., evaporated in the kugelrohr at 50–70° C./1 Torr and extracted with aqueous saturated NaHCO3 solution/Et2O (3×). The organic phase was dried over Na2SO4, evaporated and the residue was crystallized from Et2O/pentane at −20° C. to give 200 mg (65%) of (2S,4R)-benzyl-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-amine, mp 63–64° C., MS: 421 (MH+).