Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])=[CH:16][CH:15]=1)=[O:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cccn3COCC[Si](C)(C)C)cc2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3ccc[nH]3)cc2)C(=O)O1
Reaction time: 2.5 h
Yield: 28.3 %

Procedure:
A solution of N-([(5S)-N-(4-[1-(2-trimethylsilylethoxymethyl)pyrrol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide (0.79 g, 1.72 mM) in dry THF (15 ml) was stirred under nitrogen and treated dropwise with a solution of tetrabutylammonium fluoride in THF (1 M, 8.6 mM). The solution was stirred for 2.5 hours and then heated at reflux for 4 hours. The solution was evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with water, dried (Mg SO4) and evaporated. The residue was purified by column chromatography, eluting with a gradient increasing in polarity from 2% to 10% MeOH/dichloromethane to give the title product as a solid (0.16 g). Mp 202-205° C., MS: 328 (MH+). NMR: 1.97 (3H, s); 3.42 (nH+H2O); 3.58 (2H, t); 3.94 (1H, m); 4.32 (1H, t); 4.89 (1H, m); 6.40 (1H, m); 6.93 (1H, m); 7.32 (1H, m); 7.82 (2H, d); 8.01 (2H, d); 8.37 (1H, t); 12.10 (1H, s).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:34]1[O:44][C:37]2([CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[O:36][CH2:35]1>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:40]1[CH2:41][CH2:42][C:37]2([O:44][CH2:34][CH2:35][O:36]2)[CH2:38][CH2:39]1
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccccc1C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A stirred solution of 18.0 grams (0.039 mole) of 2-chlorophenylmethyltriphenylphosphonium bromide in about 50 mL of dry tetrahydrofuran was cooled in a dry ice-acetone bath, and 15.4 mL (0.039 mole) of n-butyllithium (2.5M in hexanes) was added dropwise. Upon completion of addition, the reaction mixture was stirred for 1 hour. After this time a solution of 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 5.0 mL of dry tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding about 6.9 grams of 8-(2-chlorophenylmethylene)-1,4-dioxaspiro[4.5]-decane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (1.5 g, 4.39 mmol) in N,N-dimethylacetamide (5.0 mL) was added cyclopropanecarbonyl chloride (480 μL, 5.27 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.79 g, 99%) as a pale-yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:20])[CH2:18][CH3:19])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: CCC(=O)Cl
Reactant: COc1cc2c(cc1Br)CC=C2CCN
Agent: Cl
Product: CCC(=O)NCCC1=CCc2cc(Br)c(OC)cc21

Procedure:
Starting with 2-(6-bromo-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C1CNCCN1
Solvent: CO
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 25 °C
Yield: 115.1 %

Procedure:
An anhydrous solution of piperazine (54 kg) in 150 l of methanol was stirred until a clear solution was obtained. 50 kg 4,7-dichloroquinoline were then slowly added to the solution. The latter was refluxed for 8 hours and cooled to RT. The resulting suspension was filtered and the solvent removed under reduced pressure. The oil obtained was washed with water (150 l) until solid precipitation occurred. The precipitate was filtered and washed with water to yield 72 kg of crystalline 7-chloro-4-(piperazin-1-yl)-quinoline Form B, containing 25% of water (w/w).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18]C)=[O:17])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][NH:3]1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[C:6]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=3)[CH2:7]2)[CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CCC1(CCNC1=O)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCC1(CCNC1=O)C2

Procedure:
A stirred solution of (±)-methyl 2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate from Step F (50 mg, 0.193 mmol) and lithium hydroxide (24 mg, 0.578 mmol) in THF (3 mL) and H2O (1 mL) was heated at reflux for 5 h, then allowed to cool. The mixture was poured into 10% aqueous HCl (10 mL) and extracted with EtOAc (3×20 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with CH2Cl2 to give the title compound. MS: m/z=246 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:40].[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43]([NH:49][C:50]([C:52]1[O:53][C:54]3[C:60](Br)=[CH:59][CH:58]=[CH:57][C:55]=3[CH:56]=1)=[O:51])[CH2:42]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:40].[ClH:40].[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[C:60]1[C:54]2[O:53][C:52]([C:50]([NH:49][C@@H:43]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:48][CH2:47]4)[CH2:42]3)=[O:51])=[CH:56][C:55]=2[CH:57]=[CH:58][CH:59]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
500 mg (1.75 mmol) of tert-butyl 2-bromobenzylcarbamate, 512 mg (2.02 mmol) of bis(pinacolato)diboron, 428.7 mg (4.37 mmol) of potassium acetate, 49.2 mg (0.07 mmol) of PdCl2(dppf), 518.4 mg (1.34 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 3.36 ml of 2 M sodium carbonate solution and a further 49.2 mg (0.07 mmol) of PdCl2(dppf) in 5 ml of DMF are reacted by general method D. The crude product which has been dried under high vacuum is stirred in 8 ml of a 1:1 mixture of methanol and 4 M hydrogen chloride in dioxane at room temperature for 2 h. The reaction solution is concentrated and the resulting crude product is purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 245.5 mg (44.5% of theory) of the title compound are obtained.
Reaction SMILES: C[O-].[Na+].[Na].Cl.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([NH2:12])=[NH:11]>CO>[CH2:8]([C:9]1[CH:10]=[N:11][C:10]([C:9]2[CH:13]=[CH:14][C:15]([F:16])=[C:7]([F:6])[CH:8]=2)=[N:12][CH:13]=1)[CH3:7]
Reactant: N=C(N)c1ccc(F)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cnc(-c2ccc(F)c(F)c2)nc1
Yield: 106 %

Procedure:
To a solution of sodium methoxide prepared by dissolving metallic sodium (2.8 g) dissolved in anhydrous methanol (20 cc) were added 3,4-difluorobenzamidine hydrochloride (11.6 g, 0.06 mol) and α-ethyl-β-dimethylaminoacrolein (8.9 g, 0.066 mol), followed by heating the mixture under reflux for 6 hours, thereafter distilling off methanol at the atmospheric pressure, adding toluene (20 cc) to the reaction residue to extract the product, washing the extraction solution with water, drying the toluene layer over anhydrous sodium sulfate, filtering off the drying agent, distilling off toluene, and recrystallizing the residue from ethanol (20 cc) to obtain the objective 5-ethyl-2-(3,4-difluorophenyl)pyrimidine (7.0 g) having a m.p. of 86.6° C. Its 1H-NMR (proton nuclear magnetic resonance) spectra are shown in FIG. 1.
Reaction SMILES: C([O:3][C:4](=[O:11])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH3:9])C.NC(N)=[S:14].[OH-].[Ba+2].[OH-]>C(O)C>[SH:14][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:3])=[O:11]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: NC(N)=S
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(S)C(=O)O
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 100 g (0.44 mole) of 2-bromohexanoic acid ethyl ester (Aldrich) and 39.0 g (0.51 mole) of thiourea (Fisher) in 600 mL of ethanol was stirred and heated on a steam bath for 2 hr. The solvent was evaporated under reduced pressure to give a solid residue. The solid was treated with 75 g (0.44 mole) of barium hydroxide in 1 L of 20% aqueous ethanol and the reaction mixture was stirred and heated at reflux for 20 hr. An additional 30.0 g (0.18 mole) of barium hydroxide was added and stirring and heating was continued for 20 hr. The reaction mixture was filtered and the filtrate pH was adjusted to 2 with concentrated hydrochloric acid. The mixture was extracted with three 500 mL portions of ethyl ether. The ethereal extracts were washed twice with 300 mL portions of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 52.8 g (80%) of 2-mercaptohexanoic acid as a light-yellow, viscous oil that has a sharp onion smell.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([N:30]([CH3:32])[CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:33][C:34](=[O:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:19]2=[O:42])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([N:30]([CH3:31])[CH3:32])=[N:27][CH:26]=1)[CH:20]([NH:33][C:34](=[O:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:19]2=[O:42])([OH:16])=[O:14]
Reactant: CN(C)c1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Solvent: O=CO
Product: CN(C)c1ncc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Yield: 59.9 %

Procedure:
2-Benzhydryloxycarbonyl-3-(2-dimethylamino-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.4 g) is treated with formic acid (25 cc) in accordance with the working method described in Example 17, and 2-carboxy-3-(2-dimethylamino-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.05 g) is obtained, as the inner salt, in the form of a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[CH3:33][C:34]1[N:35]=[C:36]([CH2:39][NH2:40])[NH:37][CH:38]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH2:39][C:36]1[NH:37][CH:38]=[C:34]([CH3:33])[N:35]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1c[nH]c(CN)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), C-(4-methyl-1H-imidazol-2-yl)-methylamine hydrochloride (5.15 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((4-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5.5 mg, 10.07 μmol, 21.71% yield): LCMS=525.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (2 H, d, J=8.53 Hz), 7.48-7.72 (8 H, m), 6.64 (1 H, d, J=1.00 Hz), 5.17 (1 H, s), 4.28-4.53 (2 H, m), 2.18 (3H, d, J=1.00 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: [N:1]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:19]3[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]3)=[O:16])=[CH:17][CH:18]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(-n2cnc3ccccc32)cc1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A solution of 4-(1H-benzimidazol-1-yl)benzoic acid (2.88 g, 12.09 mmol) in DMF is treated with (3R)-pyrrolidin-3-ol (1.106 g, 12.69 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (2.78 g, 14.51 mmol) and N-hydroxybenzotriazole (1.89, 13.29 mmol), stirred at 80° C. for 12 hours and concentrated in vacuo. The resultant residue is dissolved in dichloromethane, washed sequentially with water and saturated NaCl, dried over MgSO4 and concentrated in vacuo to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:CH2Cl2 5:95) provides the title product as a white solid, 2.38 g (64% yield), identified by NMR and mass spectral analyses. (MS [308.4 m/e (M+H)].
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]12[N:8]([C:16]([Cl:15])=[O:18])[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: C1CC2CCC(C1)N2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1C2CCCC1CC2
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a cooled (10° C.) solution 8-aza-bicyclo[3.2.1]octane (295 mg, 2.00 mmol) and pyridine (486 μL, 6.02 mmol) in DCM (10 mL) was added triphosgene (595 mg, 2.00 mmol) portionwise. The reaction was allowed to reach room temperature and stirred overnight. The mixture was quenched with HCl (1M aqueous, 10 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with HCl (1M aqueous), brine, dried (MgSO4) and concentrated in vacuo, to give the title compound (244 mg, 70%). 1H NMR (400 MHz, CDCl3): 1.46-1.70 (4H, m), 1.72-1.92 (5H, m), 2.04-2.11 (2H, m), 4.39-4.44 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11](N)(=[O:13])=[O:12])=[CH:4][C:3]=1[Br:15].[Cl:16]S(O)(=O)=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([Cl:16])(=[O:13])=[O:12])=[CH:4][C:3]=1[Br:15]
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=S(=O)(O)Cl
Product: Nc1c(Br)cc(S(=O)(=O)Cl)cc1[N+](=O)[O-]

Procedure:
4-Amino-3-bromo-5-nitrobenzenesulfonamide ((U.S. Pat. No. 3,987,199) 1 g, 3.17 mmol) was heated at 95° C. for 3 h in chlorosulfonic acid (10 mL). The solution was cooled then poured onto ice and then filtered. The solid was redissolved in DCM and dried over sodium sulfate. Removal of the solvent yielded the product (960 mg) which was used without further purification.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1([CH3:12])[O:10][CH2:9][CH:8]([OH:11])[CH2:7][O:6]1.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:11][CH:8]1[CH2:9][O:10][C:5]([CH3:12])([CH3:4])[O:6][CH2:7]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(C)OCC(O)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a CH2Cl2 (200 mL) solution of 2,2-dimethyl-1,3-dioxan-5-ol (17.0 g, 0.13 mol) at 0° C., triethylamine (20 mL) was added slowly. The reaction flask was flushed with nitrogen for 5 minutes. Methacryloyl chloride (13.5 g, 0.13 mol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then filtered, washed with a water solution of NaHCO3 (1M, 2×200 mL) and distilled water (2×200 mL). The filtrate was dried over MgSO4. 1,4-hydroquinone (10 mg) was added as an inhibitor and solvent was removed. The oil was dissolved in ethyl acetate (50 mL) and passed through a silica gel plug. Solvent was removed and the product was purified by distillation, yielding a colorless oil product (18.5 g, 71%). 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 1.41 (s, 3H), 1.92 (s, 3H), 3.77 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.10 (d, 1H), 4.71 (m, 1H), 5.56 (s, 1H), 6.12 (s, 1H). 13C NMR (75.5 MHz, CDCl3) δ 19.2, 20.6, 23.0, 61.6, 63.2, 99.3, 123.2, 124.5, 138.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.C([Li])CCC.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[OH:23])=[CH:10][CH:9]=[N:8]1
Reactant: c1cnn(C2CCCCO2)c1
Reactant: C1CCC2OC2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@H]1CCCC[C@@H]1c1ccnn1C1CCCCO1
Yield: 3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5.50 g, 36.1 mmol), n-butyl lithium (1.63 M solution in hexane; 24 mL, 39.1 mmol), cyclohexene oxide (3.80 g, 38.7 mmol) and THF (100 mL), to yield the title compound (270 mg, 3.0%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [Br:1]C1C=CC(O)=CC=1CCO.Br[CH:13]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][O:30][CH3:31])[CH:23]=1)[O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].BrC1C=CC(OCOCC[Si](C)(C)C)=CC=1CCO.[OH-].[K+].IC>CS(C)=O.O>[Br:1][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:23][C:24]=1[CH2:28][CH2:29][O:30][CH3:31]
Reactant: OCCc1cc(O)ccc1Br
Reactant: COCCc1cccc(OC(Br)OCC[Si](C)(C)C)c1
Agent: C[Si](C)(C)CCOCOc1ccc(Br)c(CCO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COCCc1cc(OCOCC[Si](C)(C)C)ccc1Br
Reaction time: 16 h

Procedure:
Preparation of 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl] was prepared in 65% yield by the substitution of 4-bromo-3-(2-hydroxy-ethyl)-phenol in the procedure described in Example 24(a), step (vi). 1H NMR (300 MHz, CDCl3) δ 7.43 (d, 1H, J=8.7 Hz), 6.97 (d, 1H, J=3.0 Hz), 6.82 (dd, 1H, J=8.7, 3.0 Hz), 5.19 (s, 2H), 3.88 (q, 2H, J=6.6 Hz), 3.74 (t, 2H, J=8.4 Hz), 2.99 (t, 2H, J=6.6 Hz), 1.42 (t, 1H, J=6.6 Hz), 0.94 (t, 2H, 1=8.4 Hz), −0.01 (s, 9H). {(2-[Bromo-3-(2-methoxy-ethyl)phenoxymethoxy]-ethyl}-trimethyl-silane: 2-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanol (1.9 g, 6.0 mmol) was added to a solution of potassium hydroxide (1.35 g, 24 mmol) in DMSO (16 mL). Iodomethane (1.12 mL, 18 mmol) was added, and the solution stirred for 16 h. The reaction was diluted with water (50 mL) and extracted with ether (2×40 mL). Organics were washed with brine (40 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (10% ether/hexanes) gave 1.28 g of (2-[4-bromo-3-(2-methoxy-ethyl)-phenoxymethoxy]-ethyl)-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.7 Hz), 6.96 (d, 1H, J=3.0 Hz), 6.80 (dd, 1H, J=8.7, 3.0 Hz), 5.18 (s, 2H), 3.74 (t, 2H, J=8.4 Hz), 3.60 (t, 2H, J=7.2 Hz), 3.37 (s, 3H), 2.98 (t, 2H, J=7.2 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[Cl-].[Na+]>C(OCC)(=O)C>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][S:3][C:4]2[S:5][C:6]3[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=3[N:8]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CSc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.37 g (7.7 mmol) of sodium hydride (50% in mineral oil) is added batchwise to a solution of 1.5 g (7.06 mmol) of 2-mercapto-6-nitro-benzothiazole and then stirred for 30 minutes at 50° C. Then 1.45 g (7.4 mmol) of 4-bromomethylbenzonitrile is added dropwise and stirred for a further hour at 50° C. The re-action mixture is mixed with 30 ml of ethyl acetate and 70 ml of 14% sodium chloride solution, whereupon a large proportion of the title compound is obtained as a beige precipitate. The organic phase is concentrated in vacuo, the crude product precipitated is triturated with diethyl ether and the liquid phase is separated off. The solid obtained is combined with the beige precipitate.