Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:9]=[C:8]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:33]1(N=C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.NC1C2N(C3C=CC([NH:58][C:59](C4N(C)C5C(C=4)=CC=CC=5)=[O:60])=C(OC)C=3)N=C(C3CCNCC3)C=2N=CN=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[NH2:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:59]([NH2:58])=[O:60])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:9]=[C:8]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-n2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c32)ccc1N
Reactant: COc1cc(-n2nc(C3CCNCC3)c3ncnc(N)c32)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C=Nc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: COc1cc(-n2nc(C3CCNCC3)c3ncnc(N)c32)ccc1N(C(N)=O)c1ccccc1

Procedure:
The title compound was prepared from tert-Butyl 4-[7-amino-1-(4-amino-3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl]-1-piperidinecarboxylate and phenyl isocyanate in the manner described for the preparation of N2-{4-[7-amino-3-(4-piperidyl)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide: 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.44 (s, 1H), 8.33 (d, 1H), 8.23 (s, 1H), 7.47 (d, 2H), 7.31 (m, 2H), 7.19 (s, 1H), 7.06 (m, 1H), 7.00 (m, 1H), 6.5 (bs, 2H), 3.95 (s, 3H), 3-3.2 (m, 3H), 2.71 (m, 2H), 1.9-2.0 (m, 4H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 13.02 min; MS: MH+ 459.1, M−H+ 457.2
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[CH2:15].O>C1(C)C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[F:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:15]/[B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: C=Cc1cccc(F)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Product: CC1(C)OB(/C=C/c2cccc(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 11 mg of chloro(1,5-cyclooctadiene)-rhodium(I) dimer and 0.61 mL of 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 15 mL toluene was added dropwise 1.0 mL of 3-fluorostyrene, and stirred at room temperature for 4 hours. The reaction solution was added with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resultant crude product was purified and separated by silica gel column chromatography (diethyl ether:n-hexane=1:19), to afford 311 mg of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=CC(C=C)=CC=1.[CH3:10][C@@:11]12[CH:19]([C:20]([C:22]([O-:24])=O)=C)C[C@H](C1(C)C)C[CH2:12]2>O1CCOCC1>[CH:10]([O:1][CH2:2][CH3:9])=[CH2:11].[O:24]1[CH:22]=[CH:20][CH2:19][CH2:11][CH2:12]1
Reactant: C=C(C(=O)[O-])C1C[C@H]2CC[C@@]1(C)C2(C)C
Reactant: C=Cc1ccc(O)cc1
Solvent: C1COCCO1
Product: C1=COCCC1
Product: C=COCC

Procedure:
In 150 ml of 1,4-dioxane were dissolved 15 g of poly(p-hydroxystyrene/isobornyl acrylate) obtained in the above (2) and 6 g of ethyl vinyl ether and 3.2 g of 3,4-dihydro-2H-pyrane and a catalytic amount of pyridinium p-toluenesulfonate was further added thereto, followed by conducting a reaction at room temperature for 24 hours with agitation. After the reaction, the reaction solution was poured into 2000 ml of ion-exchanged water to precipitate out. Crystal was recovered by filtration, washed with water and dried under reduced pressure to give 14.7 g of poly(p-tetrahydropyranyloxystyrene/p-1-methoxyethoxystyrene/isobornyl acrylate) as white powdery crystal. A ratio of p-tetrahydropyranyloxystyrene unit, p-1-methoxyethoxystyrene unit and isobornyl acrylate unit of the obtained polymer was found about 20:50:30 by 1HNMR measurement, and a weight-average molecular weight of the polymer was about 57000 by GPC measurement using polystyrene as a standard.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.O>COCCOC.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([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)=CC=1>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:9]=2[NH:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:7]#[N:8])=[CH:28][CH:27]=1
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COCCOc1ccc(-c2cncc(C#N)c2Nc2ccc3[nH]ccc3c2C)cc1
Temperature: 95 °C
Yield: 69.7 %

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (100 mg, 0.27 mmol), 2-[4-(2-methoxyethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98 mg, 0.35 mmol), and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) in DME (6 mL) and saturated aqueous NaHCO3 (4 mL) was heated at 95° C. for 3 h, cooled to room temperature, and treated with water. The precipitate was filtered, washed with water, dried in vacuo, and purified by flash column chromatography (MeOH/CH2Cl2, 2% to 4%) to provide 75 mg (70%) of 5-[4-(2-methoxyethoxy)phenyl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a tan solid. HPLC retention time: 8.2 min.(g); MS: 399.3 (M+H); melting range: 208-210° C.; and HRMS: 399.18056.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].S(=O)(=O)(O)O.[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccccc2F)cc1
Reaction time: 0.25 h

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 22 g, was reduced in a Parr Instrument Company Series 3910 Low Pressure Shaker-type Apparatus, using 100 ml of benzene, 2 g of five percent palladium on charcoal, and 0.5 ml of concentrated sulfuric acid. Reduction was carried out at room temperature and at an initial hydrogen pressure of 50 psig. Within 15 minutes, the hydrogen pressure had dropped to 32 psig. Hydrogen pressure was increased to 52 psig and agitation continued for two hours, with no additional hydrogen pressure drop. The reaction mixture was filtered and the filtrate was neutralized with two percent aqueous sodium carbonate. The resulting mixture was washed with water. The benzene phase was separated, dried over anhydrous sodium sulfate, and filtered. The benzene was evaporated and the residue was vacuum distilled to give 17 g of 1-ethyl-4- (2-fluorophenyl)benzene, bp 99°-101°/0.3 mm. The following elemental analysis was obtained:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=O)[O:28]C(C)(C)C)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.FC(F)(F)C(O)=O.S1[CH:45]=[CH:44][CH:43]=[C:42]1[CH:46]1[CH2:48][CH:47]1[C:49](Cl)=O.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:28])[C@H:44]([C:43]1[CH:42]=[CH:46][CH:48]=[CH:47][CH:49]=1)[CH3:45])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)C1CC1c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A precooled (0° C.) solution of t-butyl (R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methylbutoxy)phenyl)ethylcarbamate (250 mg, 0.55 mmol) and dichloromethane (10 mL) was treated dropwise with trifluoroacetic acid (2 mL). The resulting solution was maintained at room temperature for 16 h, then concentrated to afford a yellow oil that was dissolved in dichloromethane (5 mL) and added to a room temperature solution of 2-thiophen-2-yl-cyclopropane carbonylchloride (100 mg, 0.60 mmol), triethylamine (0.20 mL, 1.4 mmol) and dichloromethane (4 mL). The resulting reaction was maintained overnight, then transferred to a separatory funnel and partitioned between ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by column chromatography on silica gel (10%→50% ethyl acetate in hexanes) to afford (S)-N-((R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methyl-butoxy)-phenyl)-ethyl)-2-phenyl-propionamide (220 mg, 81% yield) as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=5.6, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.2 Hz, 2H), 7.22-7.34 (m, 5H), 7.05 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.27 (d, J=8.1 Hz, 1H), 5.26 (td, J=8.3, 5.3 Hz, 1H), 3.86-3.90 (m, 2H), 3.79 (dd, J=9.1, 6.1 Hz, 1H), 3.70 (dd, J=8.8, 6.6 Hz, 1H), 3.50 (q, J=7.2 Hz, 1H), 1.80-1.90 (m, 1H), 1.52-1.59 (m, 1H), 1.39 (d, J=7.1 Hz, 3H), 1.23-1.32 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 485.0 [(M+H)+, calcd for C30H32N2O4 485.6].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:18])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: CCOC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CNS(=O)(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
A solution of 5-bromopyridine-3-sulfonyl chloride (3.5 g, 14 mmol) (described in the synthesis of Example 170) and glycine ethylester (2.1 g, 20 mmol), diisopropyl ethyl amine (2.6 g, 20 mmol) in THF (70 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic solution was separated, dried and evaporated under reduced pressure. The residue was purified using flash column chromatography using ethyl acetate/hexanes as eluent to obtain ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (600 mg, 14%). LCMS Method I: retention time 1.31 min; [M+1]=323, 325.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:22]([N:25]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=1)[CH2:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])(=[O:24])[CH3:23]>>[C:22]([N:25]([CH2:35][C:36]1[N:37]=[C:38]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:39]=[CH:40][CH:41]=1)[CH2:26][C:27]([NH:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(=O)N(CC(=O)NC1CCCC1)Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N2-acetyl-N2-[(6-bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (0.14 g, 0.38 mmol) as the starting materials.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:28])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]C(=O)C)=[CH:10][CH:9]=2)=[O:5])C.CO.O.[OH-].[Li+]>C1COCC1>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:28])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)=[O:27]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3OC(C)=O)ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of step (a) (2.0 g, 5.26 mM) was dissolved in THF (30 mL), methanol (10 mL), and water (10 mL). The mixture was treated with lithium hydroxide (882 mg, 21.04 mM) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to 15 mL and the pH was adjusted to about 3.0 with 1 N HCl. The mixture was extracted 3 times with ethyl acetate (25 mL). The ethyl acetate fractions were combined, dried over MgSO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O-:10])=[O:9])[N:6]=1.[K+].[CH2:13](O)[CH:14]([CH3:16])[CH3:15].Cl.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O:10][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:9])[N:6]=1
Reactant: CC(C)CO
Reactant: Nc1nc(C(=O)C(=O)[O-])cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)COC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture comprising 10 g of potassium 2-aminothiazol-4-ylglyoxylate, 15 g of isobutyl alcohol and 50 ml of a 4N dioxane solution of hydrogen chloride was stirred at room temperature for 2 days. The reaction mixture was poured into water and neutralized with potassium carbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the ethyl acetate was evaporated off under reduced pressure, giving the desired compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 50 °C
Yield: 38.8 %

Procedure:
A mixture of 6,7-dimethoxyquinolin-4-ol (1.4 g, 6.8 mmol, 1.0 eq.), 3,4-difluoro-nitrobenzene (1.44 g, 8.84 mmol, 1.3 eq.) and cesium carbonate (3.6 g, 10.9 mmol, 1.6 eq.) in dry DMF (10 mL) was heated for 1 h at 50° C. in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 5:1) to yield the desired product A1 (909 mg, 2.64 mmol, 38.8%) as a yellow solid. 1H NMR (400 MHz, CDCl3, 300K) δ 4.04 (s, 3H), 4.06 (s, 3H), 6.55 (d, J=5.2 Hz, 1H), 7.34 (dd, J=7.8 Hz, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.46 (s, 1H), 8.13 (m, 1H), 8.19 (dd, J=9.8 Hz, J=2.5 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H). MS (ES) C17H13FN2O5 requires: 344, found: 345 (M+H)+. Furthermore an isomer (941 mg, 2.74 mmol, 40.2%) was isolated as a yellow solid. MS (ES) C17H13FN2O6 requires: 344. Found: 345 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2.[C:21]([Li])(C)(C)C.CN(C)C=O>CCOCC>[CH3:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:7]2
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)COS(=O)(=O)c1ccc2c(Br)cccc2c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc2cc(S(=O)(=O)OCC(C)(C)C)ccc12
Reaction time: 1 h

Procedure:
To a cooled (-80° C.) solution of neopentyl 5-bromonaphthalene-2-sulfonate (300 mg; 0.84 mmol) in anhydrous ether (12 mL) is added tert-butyllithium (1.7M in ether) (1 mL; 1.7 mmol), immediately followed by a solution of dimethylformamide (125 mg; 1.7 mmol) in ether (2 mL). The external cooling bath is removed and stirring is allowed to proceed for 1 hour. The reaction mixture is quenched with water (10 mL), the two solution phases are separated and the aqueous phase is extracted with ether (2×10 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure to afford crude neopentyl 5-methylnaphthalene-2-sulfonate.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O=C1[NH:15][CH:14](C(O)=O)[CH2:13]C1.C(CN)O>>[NH:1]1[CH:2]([C:7]2[O:9][CH2:13][CH2:14][N:15]=2)[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: NCCO
Product: O=C1CCC(C2=NCCO2)N1

Procedure:
In a similar manner, pyroglutamic acid, i.e. 5-oxo-2-pyrrolidinecarboxylic acid, where R=H and m=0 in the above formula (I), can be condensed with ethanolamine and cyclodehydrated to form the corresponding monomer 2-(2-pyrrolidon-5-yl)-2-oxazoline.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[OH-].[Na+].CN([CH:16]=[N:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)C>O.O1CCOCC1.C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:17][CH:16]=[N:10]1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccccc2F)cc1

Procedure:
A 25.0 g. portion of o-fluorophenylhydrazine hydrochloride is dissolved in 150 ml. of p-dioxane with warming and 31.0 ml. of 5 N sodium hydroxide is added. After solution is complete, 80 ml. of glacial acetic acid and 210 ml. of water are added followed by 28.1 g. of N-(dimethylaminomethylene)-p-nitrobenzamide in 100 ml. of warm p-dioxane. This reaction mixture is heated at 90°-95° C. for 1.5 hours, then cooled and poured into 1500 ml. of water. The solid is collected by filtration, washed with water, dried and crystallized from 200 ml. of ethanol, giving 13.9 g. of the desired product as a tan solid, mp. 143°-145° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1>>[CH3:19][C:14]1[CH:13]=[CH:12][C:17]2[O:18][C:9](=[O:10])[CH2:8][CH:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:16]=2[CH:15]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)/C=C/c1ccccc1
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2

Procedure:
retention times are: t-cinnamic acid=3.3 min., p-cresol=4.2 min. and the title compound=20.3 min.) or TLC (acetone/cyclohexane (20/80), acetic acid (0.5%); wavelength=254 nm) usually 6 hours. When the reaction is complete the mixture is cooled to 100° and added to a prewarmed separatory funnel (500 mL). The bottom layer containing the sulfuric acid is removed and toluene (280 mL), water (50 mL) and potassium carbonate (47%, 10 mL) are added to the separatory funnel containing the crude product. If necessary the pH of the aqueous layer is adjusted to between 5-8 with additional 47% potassium carbonate. The layers are separated and the organic layer is then washed once with water (50 mL). The organic layer is concentrated to a final volume of approximately 150 mL under reduced pressure. Isopropanol (350 mL) is then added, and distillation is continued to a volume of 350 mL. Isopropanol (150 mL) is again added and again distilled to 350 mL. Isopropanol (150 mL) is again added and again distilled to 350 mL. The mixture is then cooled to 30-40° with rapid stirring until the product crystallizes. The rapid stirring is continued after crystallization. The product is cooled to 0-5° and held at this temperature for approximately 1 hour, filtered and washed with isopropanol (200 mL) cooled to 0-5°. If the last portion of the wash is colored the wash is continued until no more color is removed. The solids are then dried at 60° under reduced pressure to give the title compound, mp (uncorrected)=83°-85°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.[Cl:21]Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:21])[C:16]([CH3:20])=[N:15]1
Reactant: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1Cl
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Into a solution of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3,5-dimethylpyrazole (31.9 g) in chloroform (200 ml) was introduced chlorine gas (7.1 g) for 10 minutes under water-cooling, and then the reaction mixture was stirred for further 30 minutes to effect the chlorination reaction. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (35.2 g) as a pale brown oil. Purification of this oil by silica gel column chromatography yielded a colorless oil. nD23 =1.5431.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH:18]=[O:19])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (2.45 g: 10 mmole) in tetrahydrofuran (10 ml), formic acid (453 μl: 12 mmole), triphenylphosphine (3.15 g: 12 mmole), and diethyl azodicarboxylate (1.89 ml: 12 mmole) are successively is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 30 minutes at the same temperature to give (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.17 g). Yield: 79%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=7.8 Hz, 9H), 2.1 to 2.6(m, 2H), 3.5 to 3.9(m, 5H), 4.4(m, 1H), 5.4(m, 1H), 8.0(s, 1H).