Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 15.1, 5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol and methane sulfonyl chloride were converted to yield Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester light brown oil, MS: 369(M).
Reaction SMILES: [CH2:1]([N:9]([CH2:19][C:20]([O:22]C)=[O:21])[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([N:9]([CH2:19][C:20]([OH:22])=[O:21])[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN(CC(=O)OC)C(=O)CCCCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCN(CC(=O)O)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
Methyl 2-(N-octyloctanamido)acetate (44.7 mg, 0.136 mmol) was dissolved in 0.5 mL of methanol and then 100 μL of 20% aqueous sodium hydroxide solution was added. The reaction mixture was then stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 3 mL of ethyl acetate and then neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 36.5 mg (0.116 mmol, 86%) of the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[NH:6]1[C:14]2[C:9](=[C:10]([CH2:15][N:16]([CH2:25][CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:17]([C:19]3[NH:23][N:22]=[C:21]([Cl:24])[CH:20]=3)=[O:18])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>CC(O)=O.CCOC(C)=O>[Cl:24][C:21]1[CH:20]=[C:19]([C:17]([N:16]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29]2)[CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[C:8]([CH2:1][N:2]([CH3:4])[CH3:3])=[CH:7][NH:6]3)=[O:18])[NH:23][N:22]=1
Reactant: C=O
Reactant: CNC
Reactant: O=C(c1cc(Cl)n[nH]1)N(Cc1cccc2[nH]ccc12)CC1CCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2cccc(CN(CC3CCC3)C(=O)c3cc(Cl)n[nH]3)c12
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl amine (109 uL of 2 molar, 0.218 mmol) in AcOH (1 mL) was added formaldehyde (7.91 uL of 38% aqueous, 0.109 mmol). After stirring for 15 min a solution of N-((1H-indol-4-yl)methyl)-3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamide (34 mg, 0.099 mmol) in acetic acid (1 mL) was added. The reaction was stirred overnight at 75° C. then cooled to room temperature and diluted with EtOAc (3 mL) and washed with saturated potassium carbonate solution (3 mL) twice and water (2 mL) once. The organic layer was then stripped in vacuo and the product purified by normal phase chromatography (DCM/MeOH, 0→20%). After isolation of the product the purity was not high enough so it was repurified by semi prep HPLC (ACN/Water+0.05% TFA) to give the desired product in 97% purity.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][C:14]1[CH:15]=[C:16]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])[S:20][C:17]2=[N:18][CH:19]=1.O>CC#N>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[S:20][C:17]2[C:16]([N:22]=1)=[CH:15][C:14]([CH2:13][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:19][N:18]=2)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CCl)cnc2s1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
Pyrrolidine (2.8 mol, 203 g) and K2CO3 (2.8 mol, 395 g) were added to a suspension of 6-(chloromethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (0.52 mol, 175 g) in CH3CN (1.7 L). The reaction mixture was stirred at room temperature for 16 h. H2O (1 L) was added and the mixture stirred for 30 min. The CH3CN was removed under vacuum and the resulting mixture was extracted with CH2Cl2 (3×1.5 L). The combined organics were washed with brine, dried (Na2SO4) and concentrated under vacuum to give 2-(2-nitrophenyl)-6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridine as a dark oil (150 g, 76% yield).
Reaction SMILES: BrC1C([NH:12]C(=O)C(=O)CC(C)(C2C=CC=CC=2)C)=CC=C2C=1COC2=O.[CH2:27]([C:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:32](=[O:39])[O:31][N:30]=1)[CH3:28].[F:40][C:41]1[CH:42]=[CH:43][C:44]([O:56][CH3:57])=[C:45]([C:47]([CH3:55])([CH3:54])[CH2:48][C:49](=[O:53])[C:50](O)=[O:51])[CH:46]=1>>[F:40][C:41]1[CH:42]=[CH:43][C:44]([O:56][CH3:57])=[C:45]([C:47]([CH3:55])([CH3:54])[CH2:48][C:49](=[O:53])[C:50]([NH:12][C:36]2[CH:37]=[CH:38][C:33]3[C:32](=[O:39])[O:31][N:30]=[C:29]([CH2:27][CH3:28])[C:34]=3[CH:35]=2)=[O:51])[CH:46]=1
Reactant: CCc1noc(=O)c2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(=O)O
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Product: CCc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cc(F)ccc3OC)cc12

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 4-ethyl-2,3-benzoxazin-1-one and 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid, melting point 157-158° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:9][CH:7]([OH:8])[C@H:6]([OH:10])[C@@H:5]([OH:11])[C@@H:4]1[OH:12].[Cl:13][CH2:14][CH2:15][N:16]([N:29]=[O:30])[C:17](=O)[O:18]C1C=CC=CC=1[N+]([O-])=O.C([O:33]CC)C>CO.CS(C)=O.O1CCCC1>[OH:8][CH:7]1[O:9][C@H:3]([CH:2]([NH:1][C:17](=[O:18])[N:16]([CH2:15][CH2:14][Cl:13])[N:29]=[O:30])[OH:33])[C@@H:4]([OH:12])[C@H:5]([OH:11])[C@H:6]1[OH:10]
Reactant: CCOCC
Reactant: NC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=NN(CCCl)C(=O)NC(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
1.79 g (10.0 mmol) of 6-amino-6-deoxy-D-glucopyranose is dissolved in a mixture of 15 ml methanol and 5 ml dimethyl sulfoxide, and the solution is cooled to 0°-5° C. This solution is added dropwise to a solution prepared by dissolving 3.28 g (12.0 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate in 20 ml of tetrahydrofuran, while stirring, at 0°-5° C. over 30 minutes. The resultant mixture is stirred at the same temperature for a further 2 hours. The thus reacted solution is concentrated at 30° C. and below, under reduced pressure. To the oily residue produced is added 100 ml of ethyl ether and the mixture is left at 4° C. overnight. The crystals thereby obtained are washed with chloroform and then with ethyl ether, dried under reduced pressure, and recrystallized from anhydrous ethanol-n-hexane (4:1) to give 2.33 g of 3-(D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea. Yield 74.3%. mp 102°-103° C. (decomp.). [α]D20 +55° (C 0.5, methanol; the value of +55° reduced to +31° after 22 hours). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C.C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:6]3=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[CH:11]=[C:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2cc(OC)cnc2[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC)cnc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To Ethyl 5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate isolated in step 3 (166 mg; 0.753 mmol) in DMF (2 mL) and THF (1 mL) cooled to 0° C. was added solid sodium hydride (60% dispersion in mineral oil; 40 mg, 1.00 mmol) and the solution allowed to warm to ambient temperature. 4-chlorobenzylchloride (181 mg, 1.12 mmol) was then added and the reaction maintained at ambient temperature. After completion (as determined by TLC analysis) the reaction mixture was partitioned between EtOAc and water, the aqueous layer extracted with EtOAc, the combined organic phases dried (MgSO4), filtered and evaporated. The residue was purified on silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes to afford the title compound as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Oc1ccc(F)cc1F
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 93.4 %

Procedure:
A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (20 g, 91 mmol), 2,4-difluorophenol (11.87 g, 91 mmol) and potassium carbonate (12.6 g, 91 mmol) in DMSO (90 mL) was heated at 120° C. for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide the title compound (28 g, 89% yield).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O[N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:2]([C:7]([O:9][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Boc-Leu-OH.H2O (49.9 g, 0.2 M) and HOSu (23.0 g, 0.2 M) were dissolved in THF (300 ml) in a 1 lit. round flask. DCC (41.3 g, 0.2 M) in THF (200 ml) solution was added dropwise at -10° C. for about 10 minutes and the mixture was stirred at room temperature overnight. Precipitated DCU was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with 1 N-HCl, NaCl solution and a small amount of water and dried with anhydrous sodium sulfate. After removal of the drying agent, the solution was concentrated, and n-hexane was added thereto to obtain Boc-Leu-OSu as a colorless powder (m.p. 106°-110° C., 59.11 g, yield: 90%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. ES-MS m/e (%): 395 (M+H+, 100).
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:9]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1([O:28][C:29](=O)[NH:30][C:31]2[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>O.C(#N)C>[CH3:38][O:37][C:35]1[CH:34]=[C:33]([O:39][CH3:40])[N:32]=[C:31]([NH:30][C:29](=[O:28])[NH:19][S:18]([C:10]2[CH:9]=[C:8]([NH:7][NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:20])=[O:21])[N:36]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(NNC(=O)C(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
0.8 g (2.5 mmol) of methyl 4-(2-isobutyrylhydrazino)-2-sulfamoylbenzoate and 0.77 g (2.8 mmol) of phenyl-N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 25 ml of acetonitrile. 0.83 g (5.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added dropwise at 0° C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2N HCl. The aqueous phase is extracted three times with CH2Cl2. After the CH2Cl2 phase has been washed with 2N HCl and water, it is dried and evaporated. The residue is triturated with diethyl ether. Filtration with suction and drying gives 0.8 g (64% of theory) of methyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]-4-(2-isobutyrylhydrazino)benzoate of melting point 169°-171° C. (decomposition).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:13]C(CC)CCBr.P(Br)(Br)Br.CC(CC)CCO>CCOCC.N1C=CC=CC=1>[CH3:13][CH:4]([CH2:5][CH3:6])[CH2:3][CH2:2][CH2:1][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCc1cccnc1
Reactant: CCC(C)CCBr
Agent: BrP(Br)Br
Agent: CCC(C)CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)CCCc1cccnc1

Procedure:
3-(4-Methylhexyl)pyridine was prepared in a similar manner to that described above with regard to 3-hexylpyridine but using 3-methyl-1-pentylbromide [prepared by adding over 1 h, at -30° C. and under N2, 22.5 g of PBr3 (0.083 mol; 7.8 ml) to a mixture of 21.6 g (0.212 mol) of 3-methyl-1-pentanol, 3.95 g of anhydrous pyridine and 88.4 ml of anhydrous sulfuric ether; the mixture was allowed to react for 1 h at -30° C. and then for 1 night at room temperature; the reaction product was extracted and washed in the usual manner and purified on a Vigreux column to provide 20.8 g of pure product].
Reaction SMILES: [Cl:1]Cl.C(O)(=O)C.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH:30]=2)=[CH:11][CH:10]=1>>[Cl:1][C:32]1[CH:31]=[C:12]([CH:11]=[CH:10][C:9]=1[O:8][CH3:7])[O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:30]=1
Reactant: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Reactant: ClCl
Solvent: CC(=O)O
Product: COc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)C(C(F)(F)F)O3)cc1Cl
Yield: 53 %

Procedure:
To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 M solution, 0.84 mmol) was added 6-(4-methoxyphenoxy)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorine in acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. After three additional hours additional chlorine in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction was quenched with aqueous 10% sodium bisulfite solution and the resulting mixture extracted with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo yielding a brown oil. The oil was dissolved in a minimum of hexanes which induced crystallization. Vacuum filtration of the mixture provided the title compound as yellow crystals (0.18 g, 53%): mp 205-207° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249 (M−H, Calc'd 399.0247). Anal. Calc−d for C18H12ClF3O5: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].Cl>[OH-].[Na+]>[C:10]([NH:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:12])[CH3:11]
Reactant: CC(C)C(C)(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(C)(C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-2,3-dimethylbutyric acid (13.1 g) in 55 ml 2N NaOH maintained at 5° C is added simultaneously dropwise but separately 17 ml acetic anhydride and 95 ml 2N NaOH so that the pH of the solution is maintained at about 8.5. After stirring at room temperature for a further 1/2 hour, the mixture is acidified with concentrated HCl and the product, (±)-2-acetylamino-2,3-dimethylbutyric acid, removed by filtration, washed with cold water and air-dried. A sample recrystallized from acetonitrile had melting point 189°-190° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[N+:16]([O-])([OH:18])=[O:17]>>[F:6][C:7]1[CH:8]=[C:9]([C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To 520 cm3 of sulphuric acid, cooled to 0° C., are added, with stirring, 60 cm3 of fuming nitric acid, over 30 minutes. 100 g of 3,4-difluorobenzaldehyde are added over 30 minutes at approximately 0° C. to the solution obtained. The temperature is allowed to return to approximately 20° C. and stirring is continued for 3 hours at this temperature. After cooling to approximately 5° C., the reaction mixture is poured, over 30 minutes and with vigorous stirring, onto 1200 g of crushed ice. The temperature is allowed to return to approximately 20° C., followed by extraction with twice 600 cm3 of toluene. The combined organic extracts are washed with 3 times 1000 cm3 of water, and concentrated under reduced pressure (20 kPa) at 50° C. 113 g of 3,4-difluoro-6-nitrobenzaldehyde are obtained in the form of a brown oil, which is used as it is in the subsequent syntheses. A purified sample of 3,4-difluoro-6-nitrobenzaldehyde gives the following characteristics:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19](Br)=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:37]([O:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>CN(C)C=O.C(Cl)Cl.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]([OH:28])=[O:27])[C:19]([C:42]#[C:41][CH2:40][CH2:39][CH2:38][CH2:37][O:43][S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)(=[O:45])=[O:46])=[CH:18][CH:17]=1)[OH:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=C(O)c1ccc(Br)c2cccc(C(=O)O)c12
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC#Cc2ccc(C(O)=Nc3c(C(C)C)cccc3C(C)C)c3c(C(=O)O)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed mixture of 0.50 g (1.15 mmoles) of N-(2,6-diisopropylphenyl)-4-bromo-naphthaline-1,8-dicarboxylic acid imide (synthesized according to WO2007062002) and 0.17 g (0.89 mmoles) of Cu(I) iodide in 20 ml anhydrous dimethylformamide (DMF) and 40 ml anhydrous methylene chloride were added 0.53 g (0.46 mmoles) of tetrakis(triphenylphosphino)-palladium (0), 0.58 g (0.80 ml, 5.5 mmol) triethylamine and a degassed solution of 0.48 g (1.90 mmol) p-toluensulfonic acid-5-hexinyl ester (synthesized according to (Y. Yang and T. M. Swager, Macromolecules 2006, 39, 2013-2015) in 2 ml methylene chloride. The reaction mixture was stirred for 60 minutes at room temperature, subsequently the solvent was evaporated until dryness and purified on silica gel ((60 Å, 60-200 μm), first with methylene chloride and afterwards with n-heptane/acetic acid (3:1) as free-flow agent. 0.6 g (86% of the theoretical yield) of a orange-yellow oil were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:6][NH:7][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH:13]3[OH:20])[CH2:11]1)[CH2:17]2)=[O:9].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:38]1[CH2:43][CH2:42][C:41]2([C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]([CH2:52][C:53]([OH:55])=[O:54])[CH2:44]2)[CH2:40][CH2:39]1>C(Cl)Cl>[CH3:25][O:24][C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:23]=1)[CH2:6][NH:7][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH:13]3[O:20][C:27]([N:38]3[CH2:43][CH2:42][C:41]4([C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]([CH2:52][C:53]([OH:55])=[O:54])[CH2:44]4)[CH2:40][CH2:39]3)=[O:29])[CH2:11]1)[CH2:17]2)=[O:9]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)CC1CC2(CCNCC2)c2ccccc21
Reactant: COc1cc(CNC(=O)C23CC4CC(C2)C(O)C(C4)C3)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(CNC(=O)C23CC4CC(C2)C(OC(=O)N2CCC5(CC2)CC(CC(=O)O)c2ccccc25)C(C4)C3)cc(OC)c1
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a solution of N-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-1-carboxamide (210 mg, 0.608 mmol) and TEA (307 mg, 3.04 mmol) in dry CH2Cl2 was added triphosgene (72 mg, 0.234 mmol) at 0° C. under N2. The mixture was stirred for 1 h, and (±)-2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (130 mg, 0.608 mmol) in CH2Cl2 was added. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 and then washed with water. The organic layer was dried, filtered and concentrated to afford crude product, which was purified by preparative TLC to give 2-(1′-((1-(3,5-dimethoxybenzylcarbamoyl)4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (50 mg, 14%). LC-MS Method 5 tR=1.341 min, m/z=617.1; 1H NMR: (400 MHz, CDCl3): δ=1.22-1.51 (m, 5H), 1.63 (s, 3H), 1.75-1.96 (m, 12H), 2.08 (m, 3H), 2.22-2.38 (m, 3H), 2.60-3.12 (m, 12H) □3.41 (s, 2H), 3.58-3.82 (m, 6H), 4.00 (m, 2H), 4.33 (d, 0.214), 4.74 (d, 1H), 6.11 (d, 1H), 6.30-6.50 (m, 2H), 6.96-7.15 (m, 4H).