Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])[CH3:3].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>>[F:17][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1=[O:18])[O:16][CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Reactant: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Yield: 90.5 %

Procedure:
By the method of Example 1, Step I, 0.60 g (0.0024 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxyphenyl)imidazolidin-2,4-dione, 1.24 g (0.0048 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E), and 0.5 g (0.0036 mole) of potassium carbonate were reacted in 25 mL of 2-utanone. After purification, 1.04 g of methyl 2-[2-[3-fluoro-4[1-(1-methylethyl)imidazolidin-2,4-dion-3-yl]phenoxymethyl]-5-chloro-phenoxy]propionate was isolated as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.24 (d, 6H, JHH=8 Hz); 1.64 (d, 3H, JHH=8 Hz); 3.68 (s, 3H); 3.96 (s, 1H); 4.44 (septet, 1H, JHH=8.0 Hz); 5.04 (q, 1H, JHH=8.0 Hz); 5.24 (s, 2H); 6.80-7.34 (m, 5H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1>O>[F:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1
Reactant: O=c1[nH]c2cc(F)ccc2o1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
In a 500-ml flask, place 100 ml of concentrated nitric acid (70%) and warm to 45° C. Add 30.6 g (0.2 m) of 5-fluoro-benzoxazol-2-one (1a; X=F) and stir at 50° C. for 3 hrs. Add 240 ml of water slowly, and stir and cool to room temperature. Collect solid, wash with water, and dry in air to give 35.0 g (88%) of 5-fluoro-6-nitro-benzoxazol-2-one (2a; X=F) as pale yellow solids.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+].C(OCC)(=O)C.[Cl-].[Na+]>CN(C=O)C.O>[N:27]([CH:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])=[N+:28]=[N-:29]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)NC1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a solution of 0.380 g of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine in 1 ml of DMF is added a solution of 0.079 g of sodium azide in 1 ml of water and the mixture is stirred at room temperature for 15 hours. After addition of ethyl acetate and saturated aqueous sodium chloride solution, the organic layer is separated and washed with aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Purifying the residue on a silica gel column (ethyl acetate:CHCl3 :CH3OH=4:4:1) yields 0.201 g of (3S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino-acetamido]-2-oxoazetidine(syn-isomer, cis-trans mixture).
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:27])([F:26])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:25])[CH2:16][C@@H:17](OS(C)(=O)=O)[CH2:18][CH3:19])=[CH:10][CH:9]=1.O1CCCC1.C([Mg]Cl)(C)(C)C>O>[CH2:18]([C@H:17]1[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([F:27])([F:26])[F:6])=[CH:9][CH:10]=2)[C:15](=[O:25])[CH2:16]1)[CH3:19]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a tetrahydrofuran solution (1 mL) containing 200 mg (0.589 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3, 368.4 mg (0.589 mmol) of tert-butylmagnesium chloride tetrahydrofuran solution (1.6 mmol/g) was added dropwise at room temperature for 5 minutes. After stirring at room temperature for further 2 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (136.4 mg). The reaction yield of the product was determined by the method described in Example 7 to be 61%.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2C12 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2ccoc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4ccoc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(benzofuran-7-yloxy)-ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (1.4 g, 7.4 mmol) and triethylamine (0.74 g, 7.4 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene chloride) afforded 0.31 g (30%) of product as a light-brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([C:9]([F:10])([F:11])[F:12])=[N:3]1
Reactant: Cn1cc(CO)c(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C=O)c(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol (1.41 g, 7.83 mmol) in DCM (25 mL) and dimethylsulfoxide (2.22 mL, 31.3 mmol) and cool to −78° C. Add oxalyl chloride (1.91 mL, 21.9 mmol) dropwise over 15 min. and stir at −78° C. for an additional 1 hr. Add triethylamine (6.55 mL, 47.0 mmol) dropwise and stir another 1 hr. Quench with water (20 mL) and dilute with DCM (50 mL) and warm to room temperature for 1 hr. Separate the organic layer; dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 80:20 hexanes:ethyl acetate), to give the title preparation (0.98 g, 71%). 1H-NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.97 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]1=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred solution of 42.8 parts of sodium hydride dispersion 50% in 200 parts of dimethyl sulfoxide was added dropwise slowly a solution of 50 parts of 2,4(1H,3H)-pyrimidinedione in 800 parts of dimethyl sulfoxide while the temperature was kept constant (20° C.) by cooling in an ice/water bath. 62.9 Parts of 1-fluoro-4-nitrobenzene were added and the whole was stirred overnight at 50° C. After cooling, the reaction mixture was poured into 2500 parts of water. The whole was washed with dichloromethane. The aqueous phase was brought to pH 5-6. The product was filtered off and stirred in 2-propanone. The product was filtered off and dried in vacuo at 60° C., yielding 60 parts (57.6%) of 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione; mp.>300° C. (int. 23).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)=[O:7].[CH3:15][I:16]>>[I-:16].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N+:9]=1[CH3:15])=[O:7]
Reactant: CI
Reactant: Cc1ccnc(C(=O)c2ccco2)c1
Product: Cc1cc[n+](C)c(C(=O)c2ccco2)c1
Product: [I-]

Procedure:
A process for preparing 2-(2-furoyl)-1,4-dimethylpyridinium iodide comprising the steps of reacting 2-cyano-4-methylpyridine under a nitrogen atmosphere with an ethereal solution of freshly prepared 2-furyl-lithium, hydrolyzing the reaction mixture under acid conditions to form 2-(2-furoyl)-4-methylpyridine, and heating the 2-(2-furoyl)-4--methylpyridine in the presence of methyl iodide to form 2-(2-furoyl)-1,4-dimethylpyridinium iodide.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2O)=[CH:9][CH:8]=1.N>>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[Cl:3])=[CH:9][CH:8]=1
Reactant: Oc1nccc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Clc1nccc2ccc(Br)cc12
Temperature: 100 °C
Yield: 114.3 %

Procedure:
To phosphorus oxychloride (46.6 mL, 0.5 mol) at room temperature was added, portionwise, 7-bromo-1-hydroxyisoquinoline (11.2 g, 0.05 mol). The mixture was heated to 100° C. for 90 min with rapid stirring. On cooling to room temperature, the mixture was poured, cautiously onto ice/water (200 mL). Dropwise addition of aqueous ammonia raised the pH=8 and the resulting precipitate was collected by filtration, washing with cold water. The solid was dried under reduced vacuum at 45° C. for 12 h. 13.86 g (115%) Beige solid isolated. 1H NMR (DMSO-d6) δ 8.4 (s, 1H), 8.34-8.38 (d, J=6 Hz, 1H), 8.03-8.07 (m, 2H), 7.91-7.96 (d, J=6 Hz, 1H); HPLC: 96%; LCMS: 242, 244, 246.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32]Cl)[O:26]1>[OH-].[Na+].CN(C)C=O>[OH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:25]1[C@H:29]([OH:30])[C@H:28]([OH:31])[C@@H:27]([CH2:32][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:26]1
Reactant: Fc1ccccc1S
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Yield: 85.4 %

Procedure:
To a solution of 2-fluorothiophenol (38 mL, 406 mmol) in 2N sodium hydroxide (100 mL) was added 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (15.0 g, 40.6 mmol) in N,N-dimethylformamide (120 mL). The mixture was warmed to 100 C for 4 hours, following the progress of the reaction by TLC. The N,N-dimethylformamide was removed under reduced pressure, and the remaining mixture was diluted with water (200 mL), neutralized with acetic acid, extracted with ethyl acetate (3×125 mL), and the combined organic layers were dried over MgSO4. After removing the solvent under reduced pressure the residue was triturated with diethyl ether and filtered, to afford 16 grams of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol as a white powder.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.O>[N:22]1([CH2:21][CH2:20][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCOCC1

Procedure:
Salicylaldehyde (34 g) is treated first with 13.4 g of 50% sodium hydride in 220 ml of dimethylformamide and then with 185 ml of a 2N toluene solution of N-(2-chloroethyl)morpholine. The mixture is heated at 105°-110° C for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 56.6 g of product as an oil, boiling point 145°-150° C at 0.05-0.1 mm of Hg.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
Amine preparation: to N—BOC-piperazine (500 mg) in DCM (5 mL) and triethylamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([NH:14][C:15](=[O:17])[CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:15]([NH:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:10][CH:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)NCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30.6 ml chlorosulfonic acid were added in one portion to 25.0 g N-phenethyl-acetamide. The reaction mixture was stirred at room temperature for one hour, then 100 ml dichloromethane were added and the reaction mixture was poured on ice water. The organic layer was separated washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 22.0 g 4-(2-Acetylamino-ethyl)-benzenesulfonyl chloride as a white solid.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[NH3:11].[H][H]>>[NH2:11][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:1]1(=[O:2])[NH:11][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC=O
Reactant: N
Reactant: [H][H]
Product: COC(=O)CCCCCN
Product: O=C1CCCCCN1
Yield: 87.8 %
Yield: 2.4 %

Procedure:
Thereafter, 198.5 g/hour of a 10.0% strength methanolic methyl 5-formylvalerate solution and 46.4 g/hour of liquid ammonia were pumped through the reactor from below, while simultaneously passing through hydrogen, at 80° C. and under 100 bar. The reaction mixture passed from the top of the reactor via a condenser into a separator, from which 243 g/hour of product mixture and 22.6 l/hour of waste gas were removed. According to quantitative gas chromatographic analysis, the reacted mixture contained 7.22% of methyl 6-aminocaproate and 0.15% of caprolactam, corresponding to yields of 87.8% of methyl 6-aminocaproate and 2.4% of caprolactam, percentages being based on the completely converted methyl 5-formylvalerate.
Reaction SMILES: [Zr:1].[P:2](=[O:6])([OH:5])([OH:4])[OH:3]>O>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zr+4:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zr+4:1].[Zr+4:1]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]
Temperature: 80 °C

Procedure:
420 g. of zirconium basic sulphate (containing 125 g. of Zr expressed as ZrO2) was slurried with 1250 ml. water and 278 g. of 85% orthophosphoric acid were added gradually with stirring. The slurry was heated to 80° C. and maintained at this temperature for one hour. It was then filtered and the residue washed with cold water until the washings were substantially free from sulphate and phosphate anions. The filter cake was dried at a temperature of 40° C. until the dried product contained 8 to 10% of total moisture. There was thus obtained 280 g. of zirconium phosphate ion-exchanger in the hydrogen form corresponding approximately to the empirical formula ZrH2.1 (PO4)1.9.2.0 H2O. The mean particle size of the product was 40 microns and 90% of the particles were contained in the size range 35 to 45 microns. These particle size characteristics corresponded closely to those of the zirconium basic sulphate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[Br:12]Br.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: O
Solvent: ClCCl
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cold solution of 2-amino-5-nitro phenol (40.0 g, 259.52 mmol) in DCM (1.0 L), was added bromine (13.38 mL, 259.52 mmol) drop wise. The resulting reaction mixture was stirred at room temperature for 45 min. After the completion of the reaction (TLC monitoring), water was added and extracted with EtOAc (3×1.0 L). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (55.0 g, 92%) was carried forward to the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1)[OH:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C([Si](Cl)(C)C)CCC>CN(C)C=O.C(OC(C)C)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([O:4][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:2][Br:1])=[CH:6][C:7]=1[NH:19][CH:20]=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: CCCC[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 72 h
Yield: 67.9 %

Procedure:
(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (9.9 g, 28 mmol) was dissolved in dimethylformamide (36 mL). Imidazole (2.3 g, 34 mmol) and tert-butyldimethylsilyl chloride (4.7 g, 31 mmol) were added. The solution was stirred under nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and tent-butyldimethylsilyl chloride (0.64 g, 4.3 mmol) were added and the reaction was stirred for an additional 20 h. The reaction mixture was then diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separatory funnel. The organic layer was washed twice with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final wash with saturated aqueous sodium chloride (27 mL). The organic layer was dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) were added and the suspension was stirred for 10 min. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was crystallized from hexanes (45 mL) to afford 8.85 g (19 mmol, 68%) of the title compound as a solid. MS m/z: [M+H+] calcd for C22H30NO3SiBr 464.1; found 464.2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1>ClCCl.CO>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([N:13]2[CH2:14][CH2:15][C:11]3([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]4[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=4)=[O:18])[CH2:8]3)[CH2:12]2)=[N:33][CH:34]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1
Yield: 137.7 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.6.). Starting with 0.43 g (1.03 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate (isomer 5′), obtained in step 12.5., and 0.45 g (2.60 mmol) of 2-fluoro-5-bromopyridine, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, 0.68 g of pure product is obtained in the form of an oil.