Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N>Br>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(Nc2ccncc2)cc1
Agent: Br
Agent: N
Product: Oc1ccc(Nc2ccncc2)cc1
Temperature: 140 °C

Procedure:
A mixture of the product from step (i) above (2.0 g) and 48% w/v hydrobromic acid (30 ml) was heated at 140° C. for 4 hours. The cooled solution was neutralised with 0.880 ammonia solution and then extracted four times with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, then dried (MgSO4) and evaporated. Purification by flash chromatography on silica, eluting with 10 to 20% v/v methanol/dichloromethane gave 4-(4-pyridylamino)phenol, 0.78 g as an off-white solid: m.p. 246°-248° C.; NMR (CDCl3 +d6DMSO) δ 8.92 (1H, b), 8.09 (2H, d), 7.31 (1H, s), 7.00 (2H, d), 6.79 (2H, d), 6.67 (2H, dd); m/e 187 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:11][NH2:12]>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][N:11]=[CH:7]2
Reactant: NN
Reactant: O=Cc1cc(Br)ccc1F
Product: Brc1ccc2[nH]ncc2c1

Procedure:
To 5-bromo-2-fluorobenzaldehyde 161 (2.0 g, 9.85 mmol.) was added hydrazine (10 mL). The reaction mixture was heated under gentle reflux for 4 hours. Excess hydrazine was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromoindazole 162 (1.04 g, 5.28 mmol.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][CH2:21][CH2:22][C:23]#[CH:24]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][CH2:22][CH2:21][O:20][CH3:19])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CCCOC
Product: COCCC#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 4-methoxy-but-1-yne yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(4-methoxybut-1-ynyl)phenyl)propyl)acetamide as a dark yellow oil. Yield (0.51 g, 51%). Compound could not be purified completely and was forwarded as such into the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)NC[C@@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 48.8 %

Procedure:
Example 40 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 10 (0.055 g) and 4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title compound (0.046 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].O>Br>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Cl)cc(C=O)c1O
Agent: Br
Solvent: O
Product: O=Cc1cc(Cl)cc(O)c1O
Yield: 32.5 %

Procedure:
5-Chloro-2-hydroxy-3-methoxy-benzaldehyde (see J. Org. Chem. 56; 1991; 5451; 20.0 g, 107 mmol) was suspended in hydrobromic acid (100 mL of 47% in water). The mixture was refluxed for 6 h and then cooled to room temperature before dilution with water (300 mL). The formed precipitate was collected by filtration and then washed with water. After air drying, the solid material was purified by soaking with CH2Cl2 (4×150 mL). There was obtained 6.0 g (32%) of 5-chloro-2,3-dihydroxybenzaldehyde as a solid. 1H NMR (300 MHz, CDCl3): 5.7 (s, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 9.8 (s, 1H), 11.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14]([O:16][CH2:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:15].C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:15])[O:16][CH2:17][CH:18]1[CH2:21][NH:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cccs2)cc1NC(=O)OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of tert-butyl 3-((((2-amino-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.12 g, 0.30 mmol) in dichloromethane (5 mL) was added TFA (1.5 mL) at 0° C. The reaction was then warmed to room temperature and stirred for 2 h. The solvents were then removed under reduced pressure. A saturated solution of sodium bicarbonate was added. The product was extracted with ethyl acetate, washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was washed with ether to obtain azetidin-3-ylmethyl (2-amino-5-(thiophen-2-yl)phenyl)carbamate (49.6 mg, 55% yield). ESI+ MS: m/z 304 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 8.78 (bs, 1H), 7.53 (bs, 1H), 7.34 (d, J=4.5 Hz, 1H), 7.22-7.16 (m, 2H), 7.04 (dd, J=5.5; 4.0 Hz, 1H), 6.76-6.70 (m, 1H), 5.18 (bs, 2H), 4.23 (d, J=6.0 Hz, 2H), 3.92 (t, J=8.5 Hz, 2H), 3.70-3.64 (m, 2H), 3.08-3.00 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Cl[CH2:9][C:10]([N:12]1[CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:21][CH:22]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[N:15][C:14]=2[CH2:13]1)=[O:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]([N:12]1[CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:21][CH:22]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[N:15][C:14]=2[CH2:13]1)=[O:11])[CH2:4][C:5]#[CH:6]
Reactant: C#CCCO
Reactant: O=C(CCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCOCC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To sodium hydride (60 wt % in mineral oil, 2.06 g, 51.4 mmol) in tetrahydrofuran (86 mL) at 0° C., add 3-butyn-1-ol (4.64 g, 5.03 mL, 64.3 mmol), then stir at 23° C. for 15 minutes. Add this solution to 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]ethanone (8.45 g, 25.7 mmol) in tetrahydrofuran (86 mL) at 0° C. and stir for five minutes. Pour reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether and ethyl acetate (2×50 mL each). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Combine the crude product with the crude product from a second reaction (run reaction under identical conditions and stoichiometry employing 2-chloro-1-[2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethanone (3.0 g, 9.1 mmol)) and purify by silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (2.90 g, 23%). MS (m/z): 363(M+1).
Reaction SMILES: P(Cl)(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:27][C@@H:28]([C@H:30]1[C:51](=[O:52])[N:32]2[CH:33]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[C:34](=O)[C@H:35]([CH3:36])[C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([SH:80])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:90]=[CH:89][C:88]([N+:91]([O-:93])=[O:92])=[CH:87][CH:86]=2)=[O:82])=[O:74])[CH2:69][CH2:68]1)(=[O:63])[NH2:62]>C(#N)C>[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:68][CH2:69][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([S:80][C:34]3[C@H:35]([CH3:36])[C@@H:31]4[C@@H:30]([C@H:28]([OH:27])[CH3:29])[C:51](=[O:52])[N:32]4[C:33]=3[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:86]=[CH:87][C:88]([N+:91]([O-:93])=[O:92])=[CH:89][CH:90]=2)=[O:82])=[O:74])[CH2:71][CH2:72]1)(=[O:63])[NH2:62]
Reactant: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 28.6 %

Procedure:
91 μl of diphenyl phosphorochloridate and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, 176 μl of diisopropylethylamine and a solution of 318 mg of (2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in step (1) above] in 2.0 ml of anhydrous acetonitrile were then added dropwise to the mixture, whilst ice-cooling, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was allowed to stand overnight in a refrigerator, after which it was freed from the solvent by distillation under reduced pressure. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by chromatography through a Lobar column (a product of Merk & Co., Inc., LiChroprep Si60, size B). Those fractions eluted with a 5:1 by volume mixture of ethyl acetate and methanol were collected and concentrated by evaporation under reduced pressure, to give 99 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:43]1([NH2:49])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([NH:49][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN1CCOCC1
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCOCC1)C1CCC2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (142 mg, 0.513 mmol) in methylene chloride (3.5 mL) were added triethylamine (226 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg), 1-hydroxybenzotriazole.monohydrate (100 mg), and morpholin-4-amine (62.7 μl), followed by agitating at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to afford 149 mg of the title compound (yield 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>C(=S)=S>[C:5]([CH:9]1[CH2:14][CH2:13][CH:12]([C:9]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:14][CH3:13])=[CH:11][CH:10]=2)[CH2:11][CH2:10]1)(=[O:7])[CH3:6]
Reactant: C1=CCCCC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCc1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 66.6 g. of anhydrous aluminum chloride in 200 ml. of carbon disulphide there are added at -15° C., with stirring, 39 g. of acetyl chloride and thereafter 41 g. of cyclohexene. The reaction mixture is stirred for 30 minutes at -15° C. and then the upper carbon disulphide layer is removed and replaced by 400 ml. of n-pentylbenzene. After the addition of a further 33 g. of aluminum chloride, while stirring, the reaction mixture is warmed up to ambient temperature and further stirred until the evolution of hydrogen chloride ceases. Thereafter, the reaction mixture is poured onto ice water, the separated aluminum hydroxide is brought into solution with hydrochloric acid and the organic phase is separated off, dried and distilled. After stripping off excess n-pentylbenzene, the 4-acetyl-1-(4-pentylphenyl)-cyclohexane thus obtained is distilled off under reduced pressure; yield 48 g.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].C[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=23)[N:11]=1>C(#N)C>[OH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=23)[N:11]=1
Reactant: COc1ccnc(-c2cnn3ccc(C#N)cc23)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccn2ncc(-c3nccc(O)n3)c2c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Chlorotrimethylsilane (0.61 mL, 4.83 mmol) and sodium iodide (0.72 g, 4.83 mmol) were added to a stirred suspension of 3-(4-methoxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 3a, 0.14 g, 0.54 mmol) in acetonitrile (11 mL) and the mixture was heated at 70° C. in a sealed tube and left overnight. The mixture was then cooled and the solvent evaporated. Water (4 mL) and 10% aqueous sodium thiosulfate solution (5 mL) were added to the residue and the suspension was stirred for 20 minutes. The suspension was filtered and the precipitate was dried in vacuo to give the title compound in quantitative yield which was used in the next synthetic step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: NCc1cccs1
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1csc(CNCCCOc2ccc(-c3csc4ccccc34)cc2)c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 2-thiophenemethylamine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=97%, [M+H]+=380.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:34]=[CH:33][S:32][CH:31]=1>CN(C=O)C.[Cu]>[CH:18]1([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Brc1ccsc1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccsc3)cc1)nn2C1CCCC1
Temperature: 153 °C
Yield: 22.3 %

Procedure:
A mixture of 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol (0.212 g, 0.718 mmol, 1 equiv), potassium carbonate (0.060 g, 0.43 mmol, 0.6 equiv), copper powder (0.015 g, 0.24 mmol, 0.33 equiv), and 3-bromothiophene (0.09 mL, 0.9 mmol, 1.3 equiv) in DMF (7.2 mL) was heated at 153° C. for 24 hr. The reaction mixture was allowed to cool to ambient temperature, concentrated, and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-cyclopentyl-3-[4-(3-thienyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light brown solid (0.060 g, 0.16 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 9.77 (1H, s), 8.46 (1H, s), 8.41 (1H, s), 7.73-7.74 (1H, m), 7.57 (2H, d, J=4.5 Hz), 7.46-7.48 (1H, m), 7.15 (1H, d, J=5.2 Hz), 6.96 (2H, d, J=8.6 Hz), 5.24-5.30 (1H, m), 2.03-2.05 (4H, m), 1.89-1.93 (2H, m), 1.70-1.72 (2H, m). RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 18.76 min. MS: MH+ 378.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2,6-bis-tert-butoxycarbonylamino-hexanoic acid to yield (3aR,4S,7aR)-4-((S)-2,6-bis-tert-butoxycarbonylamino-hexanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-methyl 4-((S)-2,6-diaminohexanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H] 442; RT=3.992 min; LCMS Method III
Reaction SMILES: [NH2:1][C:2](=[O:19])[C@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[ClH:20]>>[ClH:20].[NH2:11][C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:2]([NH2:1])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(N)=O
Agent: Cl
Product: NC(=O)[C@H](N)Cc1ccccn1

Procedure:
A solution of (R)-tert-butyl 1-amino-1-oxo-3-(pyridin-2-yl)propan-2-ylcarbamate (280 mg, 0.739 mmol) in aq. 6N HCl (8 mL) was stirred at room temperature for 2 h. It was then concentrated in vacuo to give (R)-2-amino-3-(pyridin-2-yl)propanamide hydrochloride (170 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[F:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][CH2:44][C:45]1[C:50]([CH2:51][CH3:52])=[N:49][C:48]2[N:53]([CH2:56][CH3:57])[N:54]=[CH:55][C:47]=2[C:46]=1[NH:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([NH:43][CH2:44][C:45]2[C:46]([NH:58][CH:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)=[C:47]3[CH:55]=[N:54][N:53]([CH2:56][CH3:57])[C:48]3=[N:49][C:50]=2[CH2:51][CH3:52])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)CCCC(=O)NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A mixture of 5-{[(3-bromo-4-fluorophenyl)methyl]amino}-5-oxopentanoic acid (920 mg, 2.89 mmol), HBTU (1130 mg, 2.98 mmol), 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (820 mg, 2.71 mmol) and diisopropyl ethyl amine (1 mL) in DCM/THF (1:1, 100 mL) was stirred at room temperature overnight. The mixture was concentrated, mixed with EtOAc (50 mL) and washed by NaHCO3 (50 mL) and NH4Cl (50 mL). The organic parts were collected, dried and concentrated to afford the desired product (1.84 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C=O)C.[CH3:19][C:20]1([CH3:33])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([NH2:32])[CH:23]=[CH:22][C:21]1=2.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:32][C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:33])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Terephthalic acid monomethyl ester (194 mg, 1.08 mmol) was dissolved in SOCl2 (5.39 mL) at 0° C. A drop of DMF was added and the mixture was stirred for 30 min. The SOCl2 was removed under vacuum and the crude acid chloride was dissolved in pyridine (12.5 mL). 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine 6 (200 g, 0.98 mmol) and DMAP (12 mg, 0.1 mmol) was added and the mixture was heated at 60° C. for 2 h with stirring. The mixture was poured into H2O and the product was extracted with EtOAc. Them organic layer was washed successively with HCl 2M, saturated NaHCO3, saturated NaCl, dried over MgSO4 and filtrated to give after evaporation N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-terephthalamic acid methyl ester 7 (316 mg, 88% yield) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[O:22][C:12]([CH:13](CC([O-])=O)CC([O-])=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].C(O)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[NH:33][N:32]=[C:31]2[C:39]([NH:41][NH2:42])=[O:40]>CN(C)C=O>[N+:6]([C:9]1[O:22][C:12]([CH:13]=[N:42][NH:41][C:39]([C:31]2[C:30]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)[NH:33][N:32]=2)=[O:40])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=C([O-])CC(CC(=O)[O-])c1ccc([N+](=O)[O-])o1
Reactant: COc1cc2[nH]nc(C(=O)NN)c2cc1OC
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2[nH]nc(C(=O)NN=Cc3ccc([N+](=O)[O-])o3)c2cc1OC
Reaction time: 24 h
Yield: 70 %

Procedure:
5 ml. of concentrated sulfuric acid are added dropwise to the suspension of 6 g. of 5-nitrofurfurylidenediacetate in 100 ml. of ethanol, and the mixture is stirred for 10 to 30 minutes at 50°C. Thereafter a solution of 6 g. of 5,6-dimethoxyindazole-3-carboxylic acid hydrazide in 100 ml. of dimethylformamide is added, and the mixture is allowed to stand at room temperature for 24 hours. 6.3 g. (70 %) of 5,6-dimethoxyindazole-3-carboxylic acid-(5'-nitro-furfurylidene)-hydrazide are obtained; m.p.: 334°C. This compound is identical with Compund 26 of Table 5.