Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C@@H:4]([NH:3][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-pyridin-3-yl-propan-1-one dihydrochloride (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield 26 mg, 8%; HPLC (50/50) 5.02 minutes (99%); PBMS 427/429 (MH+, 100%);
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C([O-])(O)=O.[Na+]>[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH2:9][CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH:3]=1.[CH3:1][C:2]1[CH:3]([C:10](=[O:12])[CH3:11])[C:4]2([CH2:7][CH2:8][CH:9]=1)[CH2:6][CH2:5]2
Reactant: CC(=O)OC(C)=O
Agent: CC1=CC2(CCC1)CC2
Agent: O=C([O-])O
Agent: [Cl-]
Product: CC(=O)C1C(C)=CCCC12CC2
Temperature: 50 °C
Yield: 25 %

Procedure:
A mixture of 5-methylspiro[2.5]oct-4-ene (1.41 g, 11.5 mmol), acetic anhydride (2.83 ml, 29.9 mmol), and zinc chloride (203 mg, 1.5 mmol) was heated at 50° C. for 14.5 h, cooled to 20° C., poured into a mixture of a saturated aqueous solution of NaHCO3 and ice, and extracted with pentane. The aqueous phase was extracted twice with pentane and the combined organic phases were washed with a saturated aqueous solution of NH4Cl, with a saturated aqueous solution of NaCl, dried (Na2SO4), and concentrated. FC (300 g SiO2, pentane/Et2O10:0.5) of the crude product (1.91 g) gave unreacted 5-methylspiro[2.5]oct-4-ene (765 mg) and 1-(5-methylspiro[2.5]oct-5-en-4-yl)ethanone (479 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[CH:3]=1.[OH-].[K+].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)N(C)C>[Br:1][C:2]1[CH:7]=[C:6]([O:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C(=O)N(C)C
Product: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
1,3-dibromo-5-nitrobenzene (30.0 g, 107 mmol), freshly powdered potassium hydroxide (10.8 g, 192 mmol) and tetrabutylammonium bromide (3.42 g, 10.7 mmol) were dissolved in tetramethyl urea (TMU, 90 mL). A solution of p-methoxybenzyl alcohol (17.8 g, 128 mmol) in TMU (30 mL) was added drop-wise at room temperature over a period of 1 h. The mixture was stirred for 48 h at room temperature. The reaction mixture was poured on ice (160 g) and was extracted with tert-butylmethyl ether (4×200 mL). The combined organics were dried (MgSO4) and concentrated to give the crude product which was purified by FC (2.5 kg SiO2, AcOEt/heptane 1:9) to provide 29.6 g of 3,5-dibromo-1-p-methoxy-benzyloxybenzene which was not completely pure but which crystallized upon standing. The solid was taken up in methanol (27 mL) and the formed slurry was stirred at 60° C. for 10 min. The suspension was cooled to 0-5° C. and was then filtered. The filter cake was washed with cold methanol (2×15 mL) and dried to provide 28.1 g (71%) of 3,5-dibromo-1-p-methoxy-benzyloxybenzene as an off-white solid.
Reaction SMILES: NC1N=C([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)C=C(O[C@H](C2C=CC(Br)=CC=2)C(F)(F)F)N=1.C([O-])([O-])=O.[Na+].[Na+].COC1C=C(B(O)O)C=CC=1>O1CCOCC1>[CH2:19]([O:18][C:16]([N:14]1[CH:13]([C:26]([OH:28])=[O:27])[CH2:12][C:11]2([CH2:29][CH2:30][NH:8][CH2:9][CH2:10]2)[CH2:15]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1nc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)cc(N2CCC3(CC2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C3)n1
Agent: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (80 mg, 0.12 mmol) in dioxane (1 mL)/Na2CO3 (1.0 mL, 2 M, aq) were added (3-methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)2 (8 mg, 0.01 mmol). The reaction flask was degassed and refilled with argon via balloon 3 times, and the reaction mixture was refluxed for 4 h. Then the reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by reverse phase silica gel column (H2O/NH4OH/MeOH) provided (S)-8-(2-amino-6-((S)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)-4-yl)ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([F:15])[CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].CO>[F:15][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]([OH:14])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: [H][H]
Reactant: C=CCc1cc(F)c2cccnc2c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(F)c2cccnc2c1O
Yield: 96.4 %

Procedure:
After a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser and a thermometer was replaced with Ar, 40.0 mL of methanol, 5 wt % Pd/C (0.40 g) and 7-allyl-5-fluoro-8-quinolinol (4.09 g) were thrown thereto and the mixture was stirred under slight pressurization of hydrogen. After replaced with Ar, the mixture was filtered to remove Pd/C and the filtrate was concentrated to give 3.98 g of 5-fluoro-7-propyl-8-quinolinol as a pale purple solid (yield: 96.0%).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)[CH:7]([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+].[N:26]#[C:27]Br>O.C(O)C.C(OCC)(=O)C>[CH2:6]([N:10]1[C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N:18]=[C:27]1[NH2:26])[CH:7]([CH3:9])[CH3:8]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cn1c(N)nc2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Add tin(II) chloride dihydrate (245.5 g, 1.09 mol) to a solution of N-[isobutyl]2-nitro-5-bromoaniline (49.5 g, 0.180 mol) in 2:1 ethyl acetate:ethanol (900 mL). Stir at 70° C. for 2 hours. Pour the reaction mixture into a slurry of ice in water and treat with saturated aqueous sodium bicarbonate. Add ethyl acetate (250 mL) and wash the organic phase sequentially with water (2×600 mL) and saturated aqueous sodium chloride (2×600 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Dissolve the residue in ethanol (600 mL). Add cyanogen bromide (32.6 g, 0.31 mol) and stir at room temperature for 15 hours. Add saturated aqueous sodium carbonate (500 mL) and extract with ethyl acetate (600 mL). Wash the organic phase sequentially with water (2×400 mL) and saturated aqueous sodium chloride (2×400 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Suspend the residue in diethyl ether (300 mL), stir for 15 minutes, filter, and dried under reduced pressure to provide the desired compound as a light brown solid (41.7 g, 86% yield).
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30])(=[O:8])[O:5]CC)C.Cl>C(O)C>[N+:29]([C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])=[CH:14][C:9]=1[P:4](=[O:3])([OH:5])[OH:8])([O-:31])=[O:30]
Reactant: CCOP(=O)(OCC)c1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(P(=O)(O)O)c1

Procedure:
A mixture of 1.85 g of the 2-nitro-5-(2'-nitro-4'-trifluoromethylphenoxy)-phenylphosphonic acid diethyl ester obtained in Example 1, in 20 ml of ethanol, and 40 ml of 20% hydrochloric acid, is refluxed for 24 hours and then evaporated to dryness, affording as residue the monohydrate of the corresponding free phosphonic acid in the form of yellowish brown crystals in quantitative yield. Melting point: 175°-180° C.
Reaction SMILES: ClCC(NC(C(O)=O)CCCC([NH:12][CH:13]1[C:28](=[O:29])[N:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]12)=O)=O.N1C=CC=CC=1.C[Si](C)(C)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(N(CC)CC)C.C(O)=O.CO>[NH2:12][CH:13]1[C:28](=[O:29])[N:15]2[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]12
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CCCC(NC(=O)CCl)C(=O)O)[C@H]2SC1
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=CO
Solvent: c1ccncc1
Solvent: CO
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a stirred slurry of 100 milligrams of 7-(5-(chloroacetamido)-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 10 milliliters of absolute methylene chloride was added 0.1 milliliters of pyridine and 0.15 milliliters of trimethylchlorosilane. The reaction mixture was stirred for two and one-half hours at room temperature. Then the reaction mixture was cooled to -15° C. and 0.2 milliliter of pyridine (in one lot), and 1.2 milliliter of 10 percent phosphorus pentachloride in absolute methylene chloride added dropwise, and the mixture stirred at -15° C. for two and one-half hours. Then 2 milliliters of absolute methanol were added, and the reaction mixture stirred for thirty minutes at -15° C. and for another thirty minutes at room temperature. Then 0.3 milliliter of 50 percent formic acid was added and the pH adjusted to 2 by adding triethylamine and stirring for forty-five minutes. The reaction mixture became cloudy. Then the pH was adjusted to 3.4, and the reaction mixture stirred for two hours in an ice bath and filtered. There was obtained 15 milligrams of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. It was identified by bioautogram and UV, which showed λ max. 262 nm (ε 5800).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5]([CH2:7][OH:8])[CH2:4][C@H:3]1[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:17][S:18]([O:8][CH2:7][C@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:4]1)(=[O:20])=[O:19]
Reactant: CN1C[C@H](CO)C[C@H]1COc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C[C@H](COS(C)(=O)=O)C[C@H]1COc1cccnc1

Procedure:
To a 386 mg (1.84 mmol) sample of 3-(trans-1-methyl-4-hydroxymethyl-2(S)-pyrrolidinylmethoxy)pyridine (from Example 48a above) dissolved in 12 mL of methylene chloride were added 262 μL (3.38 mmol) of methanesulfonyl chloride, 470 μL of triethylamine and a catalytic amount of DMAP, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with water, the product extracted from the mixture, the solvent removed, and the product purified by column chromatography on silica gel, eluting with 20:1 chloroform:methanol to afford 320 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1)([OH:21])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[H-].[Na+].[CH3:35]N(C)C=O>>[F:32][C:2]([F:1])([F:31])[C:3]([O:21][CH3:35])([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOc1ccc(C(O)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccccc3)c2)(OC)C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
1,1,1-Trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propan-2-ol (0.2 g) in dry N,N-dimethylformamide (2 cm3) was added to a suspension of sodium hydride (0.1 g of a 50% dispersion in oil--washed free of oil with n -hexane) in N,N-dimethylformamide (2 cm3) at the ambient temperature (ca. 22° C.) under an atmosphere of nitrogen. After stirring for 20 minutes a solution of methyl iodide (0.1 g) in N,N-dimethylformamide (3 cm3) was added in one portion. After 20 minutes no starting material could be detected by gas liquid chromatographic analysis. The mixture was carefully diluted with water (30 cm3) then solid sodium chloride was added and the mixture shaken with diethyl ether. The layers were separated and the aqueous layer extracted with a further three portions of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure. The resulting pale yellow oil was purified by chromatography on silica gel, eluting with n-hexane containing 10% by volume ethyl acetate to give 1,1,1-trifluoro-2-methoxy-2-(4-ethoxyphenyl)-3-(3-phenoxy-4-fluorobenzyloxy)propane as a colourless oil (0.2 g).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=[CH:8][CH:7]=1>CCO>[CH3:4][O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cccc(CCN)n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
Hydrazine monohydrate (24.94 mL, 514.18 mmol) was added to a solution of 2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 102.84 mmol) in EtOH (300 mL) at room temperature. The mixture was heated under reflux for 1 hr, and allowed to be cooled to room temperature. The insoluble substance was removed by filtration, and washed with a mixed solvent of diethyl ether/IPE (1:1). The filtrate was concentrated under reduced pressure, and to the obtained residue was added toluene (about 250 mL), and the mixture was concentrated again under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, solvent gradient; 10→100% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 95 mmol, 92%) as a colorless oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH:27]=[CH:26][C:25]=1[C:44]1[N:49]=[CH:48][C:47](O)=[CH:46][N:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(OC[C@H](F)CCCCCC)=CN=1>C1COCC1>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][C@H:33]2[CH2:34][CH2:35][C@H:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:37][CH2:38]2)[CH:27]=[CH:26][C:25]=1[C:44]1[N:45]=[CH:46][C:47]([O:16][CH2:15][C@H:14]([F:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:48][N:49]=1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ncc(O)cn3)c(F)c2F)CC1
Reactant: CCCCCC[C@@H](F)CO
Agent: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CC[C@H]3CC[C@H](CCCCC)CC3)c(F)c2F)nc1
Yield: 61.3 %

Procedure:
--Quantities: DEAD (448 mg, 2.58 mmol) in THF (3 ml), (R)-(+)-2-fluorooctanol (379 mg, 2.58 mmol), hydroxypyrimidine 48 (1.0 g, 2.58 mmol), triphenylphosphine (676 mg, 2.58 mmol). The experimental procedure was as described for compound 34. The crude product was purified by flash chromatography (5 to 7% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 49 (820 mg, 61%) (from EtOH), transitions/° C. K 102.2 N* 128.3 I; [α]D26 -2.4° (c 2.0 in CHCl3); νmax /cm-1 (KBr) 2920, 2845, 1540, 1460, 1435s, 1285 1085, and 900; δ 0.80-1.03 (10H, m), 1.06-1.45 (16H, m), 1.55 (4H, m), 1.82 (6H, m), 2.71 (2H, t J 8, ArCH2), 4.22 (2H, dd, 3JHF 22 and J 4, OCH2), 4.86 (1H, d of sext, 2JHF 48 and J 4, CHF), 7.01 (1H, ddd, J 7.5, 7 and 1.5, 5'-H), 7.67 (1H, ddd, J 7.5, 7 and 1.5, 5'-H) and 8.53 (2H, s, 4- and 6-H); m/z 518 (M+), 489, 475, 461, 447, 365 and 353.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][N:35]([CH2:40][CH:41]1[CH2:43][O:42]1)[S:36]([CH3:39])(=[O:38])=[O:37]>C(O)C>[CH3:31][O:32][CH2:33][CH2:34][N:35]([S:36]([CH3:39])(=[O:37])=[O:38])[CH2:40][CH:41]([OH:42])[CH2:43][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1
Reactant: COCCN(CC1CO1)S(C)(=O)=O
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CCOC)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 4.19 g (20 mmol) of N-(2-methoxyethyl)-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2d), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum, and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([S:13][CH2:14][C:15]#[N:16])=[C:7]([C:9](OC)=[O:10])[S:8][C:4]=2[CH:3]=1.O.[OH-].[Li+]>CN(C=O)C.Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:13][C:14]([C:15]#[N:16])=[C:9]([OH:10])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2cc(Cl)ccc2c1SCC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1sc2c(sc3cc(Cl)ccc32)c1O
Yield: 43.5 %

Procedure:
A solution of methyl 6-chloro-3-[(cyanomethyl)thio]-1-benzothiophene-2-carboxylate (1.01 g, 3.4 mmol) in DMF (20 mL) was cooled to 0° C., and lithium hydroxide hydrate (171 mg, 1.2 eq) was added in a single portion. After 1h, the solution was warmed to room temperature and stirred for an additional hour. The reaction solution was diluted with aq. hydrochloric acid and ethyl acetate. The organic layer was washed with water and brine, dried, filtered, evaporated, and recrystallized (EtOH) to provide 6-chloro-3-hydroxythieno[3,2-b][1]benzothiophene-2-carbonitrile (393 mg, 43%) as an off-white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH2:20].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH2:12]([N:11]1[C:7]([NH:6][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:8]([C:19](=[O:21])[NH:20][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[N:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Reactant: CC(C)CC(=O)Cl
Agent: O=S(=O)(O)O
Product: CC(C)CC(=O)NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)CC(C)C
Temperature: 0 °C

Procedure:
Concentrated sulphuric acid (7.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-1-benzyl-4-carbamoyl-1,2,3-triazole (10.85 g.; prepared as described by J. R. E. Hoover and A. R. Day, J.Amer.Chem.Soc., 1956, 78, 5832) in isovaleryl chloride (50 ml.), and the mixture was then stirred at room temperature overnight. The resulting solution was poured into ice-water, and the precipitated solid filtered off, stirred well with water, again filtered off, and dried, to give 1-benzyl-5-isovaleramido-4-isovalerylcarbamoyl-1,2,3-triazole (16.4 g.), m.p. 125°-128° C. An aliquot was recrystallised from di-isopropyl ether to give pure 1benzyl-5-isovaleramido-4-isovalerylcarbamoyl-1,2,3-triazole, m.p. 130°-131° C.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:7][C:6]([C:19]23[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[C:23](=[O:29])[NH:22][C:20]3=[O:21])=[C:5]([F:30])[CH:4]=1.C(OCC)C>C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[C:3]([Cl:2])=[CH:4][C:5]([F:30])=[C:6]([C:19]34[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[C:23](=[O:29])[NH:22][C:20]4=[O:21])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)C2(c3cc(Oc4ccc([N+](=O)[O-])cc4)c(Cl)cc3F)CCCCC12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(Oc2cc(C34CCCCC3C(=O)NC4=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a stirred solution of 20 mL of water in 200 mL of glacial acetic acid was added 6.0 g (0.014 mole) of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-3,4,5,6-tetrahydrophthalimide. This mixture was stirred at room temperature while 6.0 g (0.11 mole) of iron filings were slowly added. After complete addition the mixture was stirred at room temperature for one hour. Diethyl ether was added and the resultant mixture was filtered through a pad of celite. The filtrate was washed with 200 mL of water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a solid. This solid was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 4.0 g of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-3,4,5,6-tetrahydrophthalimide as a solid, m.p. 213°-215° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[S:20])[CH3:17]>C(OCC)C>[CH2:16]([N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:17]
Reactant: CCNC(=S)NCc1ccccn1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCOCC
Product: CCN1C(=NCc2ccccn2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3 g of 1-ethyl-3-(2-pyridylmethyl)-thiourea were reacted according to the prescription given in Example 23 and 150 ml of diethyl ether were added to the reaction mixture. The hygroscopic 3-ethyl-4-(4-chloro-3-sulfamoylphenyl)-2-(2-pyridylmethylimino)-1,3-thiazolidine-4-ol-hydrobromide which had separated as crystals was rapidly filtered off, dissolved in 50 ml of water and converted into the end product as described in Example 28. Colorless solid body, decomposition beginning at 135° C, γC=N 1615 cm-1.