Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=1>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:34][CH:35]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-phenyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H26N4O3 (m/e) 394, obsd 395 (M+H).
Reaction SMILES: [CH:1](O)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[CH:55]=2)=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42]>CN(C=O)C>[Cl:60][C:56]1[CH:55]=[C:54]([C:51]2[CH:52]=[CH:53][C:48]([CH2:47][C@@H:38]([NH:37][CH:1]=[O:2])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:49][CH:50]=2)[CH:59]=[CH:58][CH:57]=1
Reactant: O=CO
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC=O)C(=O)O
Reaction time: 0.08 h
Yield: 4.2 %

Procedure:
Formic acid (3 mg, 32 μmol) was combined with HATU (12 mg, 32 μmol) and DMF (0.2 mL) and stirred for 5 minutes. DIPEA (17 μl, 96 μmol) was added, followed by (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (79 mg, 38 μmol) pre-dissolved in DMF (0.5 mL) and DIPEA (17 μl, 96 μmol). The resulting mixture was stirred for 15 minutes. The solvent was removed in vacuo and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C20H22ClNO4, 376.12. found 376.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:31][CH3:32])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH2:27][CH2:28][O:29][CH3:30])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:31][CH3:32])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH2:27][CH2:28][O:29][CH3:30])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COCCc1cc(N2CCN(C)CC2)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
0.5 g (5 mmol) of 1-methyl-piperazine in 3 ml of DMF was added to a solution of 0.45 g (1.13 mmol) of 3-benzenesulphonyl-7-chloro-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 3 hrs. The reaction solution was evaporated, the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 12:1) and crystallization from EtOH yielded 0.255 g (67%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine as colorless crystals, m.p. 160-161°.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH:8]=1)=[O:5].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C>[Br:35][C:25]1[CH:24]=[N:23][N:22]([CH3:26])[C:21]=1[C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:27])[CH3:1])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CC(=O)Nc1ccc(OCCN2CCCC2)c(-c2ccnn2C)c1
Solvent: CN(C)C=O
Product: CC(C)=CC(=O)Nc1ccc(OCCN2CCCC2)c(-c2c(Br)cnn2C)c1
Yield: 24.8 %

Procedure:
3-Methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-butyramide (20 mg, 0.054 mmol) was treated with NBS (10 mg, 0.054 mmol) in DMF (2 mL) at room temperature for 2 hours. The crude was purified by HPLC to provide the title compound as an off-white solid (6 mg, 25%). Exact mass calculated for C21H27BrN4O2 446.1, found 447.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](O)=O)[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH2:29])[C:24]=2[NH2:28])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl.CCOC(C)=O.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:28][C:24]3[C:25]4[C:20]([CH:21]=[CH:22][C:23]=3[N:29]=2)=[CH:19][C:18]([Br:17])=[CH:27][CH:26]=4)[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2cc(Br)ccc2c1N
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CC2CC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C(c2nc3ccc4cc(Br)ccc4c3[nH]2)CC2CC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 854.2 %

Procedure:
To a solution of 2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (0.08 g, 0.34 mmol) in CH2Cl2 (3.5 mL) was added 6-Bromo-naphthalene-1,2-diamine (0.09 g, 0.041 mmol), HATU (0.16 g, 0.43 mmol), and DIPEA (0.3 mL, 1.72 mmol). The resulting solution was stirred at room temperature for 1.5 h and diluted with EtOAc. The organic layer was washed with H2O and brine. The aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na2SO4 and separated. The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes) to provide an oil that was dissolved in AcOH (7.0 mL). The solution was stirred at 40° C. (external, oil bath) for 2 h. The solution was diluted with EtOAc and slowly basified with saturated sodium bicarbonate and NaOH (2N). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil was purified by column chromatography (SiO2, 10→100% EtOAc (2% MeOH) in hexanes) to provide 3-(7-Bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.15 g, 97%). LCMS-ESI+: calc'd for C21H22BrN3O2: 427.09 (M+); Found: 428.35 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:41])[C@@H:37]([NH:38][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:18]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:39][OH:40]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.300 g, 0.703 mmol), L-serine methyl ester hydrochloride (0.131 g, 0.844 mmol), 1-hydroxy benzotriazole (0.104 g, 0.773 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.148 g, 0.773 mmol) were combined in amine-free N,N-dimethylformamide (2.8 mL), followed by addition of N,N-diisopropylethylamine (0.307 mL, 1.76 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined, organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform, to afford 0.330 g of the title compound as a pale yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(OC)c4)c3)csc12
Product: COc1cccc(C(=O)Nc2cccc(OCc3csc4c(C(=O)NCCO)cncc34)c2)c1

Procedure:
3-[3-(3-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(3-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 13 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: CCOC(=O)N1CCC(N)CC1
Product: CCOC(=O)N1CCC(NC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester as in General Procedure 10 to give the title compound. LCMS: m/z=601.99 (M+H+); retention time=0.85 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=O)[C:11]([CH3:18])([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Na+].BrC1C=C(C(=O)CC(OCC)=O)C=[N:27]C=1CC.IC>CN(C=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:18])([CH3:17])[C:12](=[O:13])[O:14][N:27]=2)[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)CC(=O)c1cnc(CC)c(Br)c1
Reactant: CCOC(=O)C(C)(C)C(=O)c1cnc(CC)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ncc(C2=NOC(=O)C2(C)C)cc1Br
Temperature: 25 °C
Yield: 54 %

Procedure:
Step-2: Ethyl 3-(5-bromo-6-ethylpyridin-3-yl)-2,2-dimethyl-3-oxopropanoate: To a 0° C. cooled and stirred suspension of sodium hydride (60% dispersion inoil, 120 mg, 5 mmol), in DMF (3 mL) was added ethyl 3-(5-bromo-6-ethylpyridin-3-yl)-3-oxopropanoate (0.5 g, 1.66 mmol) in DMF (7 mL) over a period of 15 min. The reaction mixture was then stirred for 15 min at the same temperature and Iodomethane (365 μl, 5.83 mmol) was added to the above mixture. The resulting mixture was then warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with water (30 mL) followed by ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 300 mg (54%) of the title compound as white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.77 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 2.96 (q, J=7.0 Hz, 2H), 1.46 (s, 6H), 1.25 (t, J=7.0 Hz, 3H), 1.03 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 328, 330 [(MH+, Br79,81].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1.C([O-])(O)=O.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ncn(-c2ccc(N)cc2F)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of 1-(2-Fluoro-4-nitro-phenyl)-3-methyl-1,2,4-triazole (Intermediate 28) (56.6 g, 0.255 mol) and SnCl22H2O (292 g, 1.29 mol) in ethanol (800 ml) was stirred at 70° C. under N2 for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice and the pH was made slightly basic by addition of NaHCO3 (solid) and extracted with ethyl acetate (3×). The combined organic phase was washed with brine (2×), dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless solid (48.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.CS(O[CH:41]1[CH2:45][CH2:44][O:43][CH2:42]1)(=O)=O>>[O:43]1[CH2:44][CH2:45][CH:1]([O:2][C:3]2[C:8]3[C:9]([C:31]4[CH:35]=[N:34][N:33]([CH:45]5[CH2:41][CH2:42][O:43][CH2:44]5)[CH:32]=4)=[N:10][NH:11][C:7]=3[CH:6]=[CH:5][N:4]=2)[CH2:41][CH2:42]1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OC1CCOC1
Product: c1cc2[nH]nc(-c3cnn(C4CCOC4)c3)c2c(OC2CCOCC2)n1
Yield: 24 %

Procedure:
Prepared according to the general procedure described in Example 92, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with tetrahydrofuran-3-yl methanesulfonate to give the title compound as a mixture of enantiomers. The enantiomers were separated via supercritical fluid chromatography to give the separated enantiomers. (7.9 mg, 7.7 mg, total yield 24% over two steps). LC-MS (Method G): m/z=286.1 [M+H]+; 2.97 min. 1H-NMR (400 MHz, DMSO): δ 13.27 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.85 (d, J=6.0, 1H), 7.09 (d, J=6.0 1H), 5.17-5.09 (m, 1H), 4.06 (s, 3H), 4.05-3.98 (m, 2H), 3.95 (dd, J=9.4, J=3.7, 1H), 3.91-3.83 (m, 1H), 2.47-2.36 (m, 1H), 2.36-2.25 (m, 1H).
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH:19]([NH:22]C(C)C)(C)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:22][CH2:19][CH3:20])=[O:4]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 75.9 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 3.1 g (31 mmol) of diisopropylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 4.1 g of theanine (yield: 75.9%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[F:23])[N:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2>C(Cl)Cl>[Cl:5][C:6]1[N:7]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:23])[N:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Temperature: 25 °C

Procedure:
A 1N solution of boron tribromide in methylene chloride (18.0 mL, 0.018 mole) was diluted with 17 mL of methylene chloride and was then cooled to below -10° C. under a nitrogen atmosphere. A solution of 3-chloro-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydroindazole in 25 mL of methylene chloride was added dropwise at a rate to maintain the temperature below -10° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature at which it stirred for sixteen hours. The mixture was then poured into ice-water, and the resulting mixture was stirred for 30 minutes. This mixture was filtered, and the filtrate was passed through a short column of silica gel. The organic phase was separated, dried with anhydrous sodium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 0.60 g of 3-chloro-2-(2-fluoro-4-hydroxyphenyl)-4,5,6,7-tetrahydroindazole as a nearly white solid, m.p. 214°-216° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH2:32])[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.1 g, 0.149 mmol) in dry dichloromethane (4 ml) is treated dropwise with TFA (2 ml). The mixture is stirred at room temperature for 12 h and then concentrated in vacuo. The residue is co-evaporated with chloroform three times to remove excess trifluoro acetic acid and purification of the residue by preparative HPLC affords the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1

Procedure:
A solution of 5 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one in 50 ml of methanol is hydrogenated for 2 h at RT under normal pressure in the presence of 0.5 g of Nishimura catalyst. The catalyst is removed by filtration and the filtrate is then concentrated in a rotary evaporator and dried under a high vacuum. TLC Rf (D)=0.5; FAB-MS (M+H+)=312.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:4])[CH:2]=[CH2:3].C(N1CCCC1=[O:21])=C>C(OCC)(=O)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:4])[CH:2]=[CH2:3].[C:1]([O:5][CH2:6][CH2:7][OH:21])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CN1CCCC1=O
Agent: C=CC(=O)OCCCCCC(C)C
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCO

Procedure:
This copolymer was prepared using a procedure similar to the one described above for isooctyl acrylate/N-vinyl-2-pyrrolidone/Elvacite™ 1020. The inherent viscosity of the polymer in ethyl acetate was 0.69 dl/g.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/Nc2ccccc2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Yield: 42.8 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 26.2 mL (0.287 mmol) aniline. The reaction mixture is stirred at room temperature for 1 week and then concentrated in vacuo. The residue is dissolved in EtOAc and triturated with hexane to give a yellow powder. The yellow powder is purified by silica gel chromatography, (hexane/EtOAc) to give an oil. The oil is triturated with hexane to give 26 mg (42.8%) product as an orange powder. HRMS (ESI) m/z calcd for C29H33NO8 523.22074, found: 524.22692 (M+H)+1.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28]2>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32]([CH:31]=[CH:30][C:29]([C:2]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH3:15])=[CH:7][C:3]=3[C:4]([NH2:6])=[O:5])=[CH:28]2)=[CH:33][CH:34]=1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Product: CCC(C(=O)Nc1ccc(-c2ccc3ccc(OC)cc3c2)c(C(N)=O)c1)c1ccccc1

Procedure:
50 mg (0.12 mmol) of the compound from Example 5A are reacted with 37 mg (0.18 mmol) of 6-methoxynaphthalene-2-boronic acid in analogy to the synthesis of Example 1. 27 mg (44% of theory) of product are obtained.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[CH2:10][C:11](OCC)=[O:12].Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[O:2]1[C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:10][C:11]1=[O:12]
Reactant: CCOC(=O)CCl
Reactant: Oc1ccccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Product: O=C1COc2ccccc2O1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a stirred solution of 120 grams of catechol and 10 grams of Aliquat® 336 (brand of tricaprylmethylammonium chloride, of General Mills Chemical Company of Minneapolis, Minnesota) at 80° C. is added ethyl chloroacetate (87 grams, 1 mole) over a one hour period. The reaction mass is stirred for one hour and then cooled. 1000 ml of dilute (5%) hydrochloric acid is added with stirring. The aqueous layer is discarded. The organic layer is washed twice with a minimum amount of water. The toluene is distilled off under reduced pressure to afford 119 grams of crude product. Recrystallization from ethanol afforded 92 grams of 1,4-benzodioxan-2-one.