Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2ccccc2)C(=O)O)C(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@H](CC[C@H](Cc1ccc(O)cc1)C(=O)O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To a round bottom flask was added (2R,5R)-2-benzyl-5-(4-methoxybenzyl)hexanedioic acid (30 mg, 0.084 mmol) and 30% HBr in acetic acid (0.5 mL). The reaction was stirred at 120° C. for 16 h. Then the solvent was removed. The residue was purified by RP prep-HPLC (Method A). The fraction was concentrated to give (2R,5R)-2-benzyl-5-(4-hydroxybenzyl)hexanedioic acid (10 mg, 0.029 mmol, 35% yield) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1C=CC=CC=1.C(=O)(O)[O-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([NH2:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CO.C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:5][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1)=[O:4]
Reactant: CC(C)(C)C(N)=O
Reactant: COc1cccc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(NC(=O)C(C)(C)C)n1
Yield: 74.5 %

Procedure:
A suspension of trimethylacetamide (18.08 g, 178.744 mmol), Cs2CO3 (68.823 g, 211.242 mmol), Pd2(dba)3 (1.488 g, 1.625 mmol) and Xantphos (4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene) (1.880 g, 3.249 mmol) in dry, degassed 1,4-dioxane (800 ml) under argon was sonicated for 0.25 h and then treated with 2-chloro-6-(methyloxy)pyridine (19.32 ml, 162.494 mmol). The mixture was then heated at reflux for 24 h. The mixture was evaporated, treated with water (1 L) and extracted 3×DCM (1 L and then 2×500 ml). The organic extracts were dried (MgSO4), evaporated and chromatographed (50-100% DCM/40-60 Petroleum ether then 0-5% methanol/DCM) to give title compound as a yellow solid (25.191 g, 121.111 mmol, 75%). Impure fractions were recolumed (eluting as above) to give more product (4.990 g, 23.990 mmol, 15%). Total yield of 90%.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]3)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(Cl)Cl.CCOCC>C1COCC1>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]3[CH2:27][CH2:26][CH:25]([C:1]([O:4][CH3:5])=[O:6])[C:24](=[O:28])[CH2:23]3)[CH2:18][CH2:17]2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: COC(=O)OC
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CCCC(=O)C3)CC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CCC(C(=O)OC)C(=O)C3)CC2)CC1
Reaction time: 2 h

Procedure:
7.5 mmol of KH and 40 ml of dimethyl carbonate are added to a solution of 2.0 g of 3-[trans-4-(trans-4-n-propylcyclohexyl)-cyclohexyl]-cyclohexanone (Example 1) in 40 ml of THF, and the mixture is boiled for 2 hours. Customary working up (silica gel; 6.5:3:0.5 petroleum ether: methylene chloride:ether) gives methyl 4-[trans-4-(trans-4-n-propylcyclohexyl)-cyclohexyl]-2-oxocyclohexanecarboxylate, which is predominantly in the enol form, m.p. 154°, c.p. 192°.
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCOC3C=CC(NC(OC(C)(C)C)=O)=CC=3)=C(C(O)=O)N=1)CC2)=O.[S:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[NH:58][C:59]([C:61]1[CH:62]=[CH:63][CH:64]=[C:65]2[C:70]=1[CH2:69][N:68]([C:71]1[S:72][C:73]([CH2:79][CH2:80][CH2:81][O:82][C:83]3[CH:88]=[CH:87][CH:86]=[C:85]([NH:89]C(OC(C)(C)C)=O)[CH:84]=3)=[C:74]([C:76]([OH:78])=[O:77])[N:75]=1)[CH2:67][CH2:66]2)=[O:60]>>[NH2:89][C:85]1[CH:84]=[C:83]([CH:88]=[CH:87][CH:86]=1)[O:82][CH2:81][CH2:80][CH2:79][C:73]1[S:72][C:71]([N:68]2[CH2:67][CH2:66][C:65]3[C:70](=[C:61]([C:59](=[O:60])[NH:58][C:50]4[S:49][C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=5[N:51]=4)[CH:62]=[CH:63][CH:64]=3)[CH2:69]2)=[N:75][C:74]=1[C:76]([OH:78])=[O:77]
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)c1
Agent: CC(C)(C)OC(=O)Nc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: Nc1cccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)c1

Procedure:
The title compound 9 was prepared by following the procedure set forth in Example 6 but substituting compound 4 in Example 6 with compound 5: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (1H, s), 8.03 (1H, m), 7.79 (1H, d), 7.67 (1H, m), 7.42 (4H, m), 7.02 (1H, m), 6.33 (3H, m), 4.83 (2H, s), 3.90 (2H, t), 3.72 (2H, t), 3.16 (2H, m), 3.03 (2H, t), 1.98 (2H, m); MS (ESI(+)): m/z 586 (M+H).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[C:14]([C:18]1[CH:22]=[C:21]([C:23](=O)[CH2:24]Br)[N:20]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:22]=[C:21]([C:23]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:24]=2)[N:20]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C(=O)CBr)n(Cc2ccccc2)n1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(C)(C)C)nn3Cc3ccccc3)cs2)c(C)s1
Yield: 81 %

Procedure:
A solution of 823 mg (3.3 mmol of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 1.36 g (3.3 mmol) of 1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-l-one in a manner similar to Example 8, step (a) to give methyl 4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (1.25 g, 79%) as a crystalline solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.11 (s, 1H), 8.05 (s, 1H), 7.28-6.99 (m, 5H), 6.70 (s, 1H), 5.88 (s, 2H), 3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C24H25N3O2S3, 484.1 (M+H), found 483.9.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9].[BH4-].[Na+]>CCO>[Cl:16][C:12]1[CH:11]=[C:10]([CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[OH:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of methyl (3-chlorophenyl)(phenyl)methanone (1 g, 4.63 mmol) and sodium borohydride (352 mg, 9.26 mmol) in EtOH (6 mL) was stirred at 25° C. for 2 h. After removal of the solvent, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product (950 mg, 94%) as yellow oil which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.5 g, 5.03 mmol) and dimethylformamide (30 mL). Add sodium hydride (0.27 g, 60%n in oil, 6.5 mmol). After 30 minutes, add 4-fluorobenzyl bromide (1.0 mL, 8.03 mmol). Heat to 80° C. After 2 hours, cool to ambient temperature and partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solutions. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:4]=[O:5])[CH3:2].C(O)(=O)C1C=CC=CC=1>>[CH2:1]([C:3](=[CH:6][CH2:7][C@H:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:14])[CH3:15])[CH2:4][OH:5])[CH3:2]
Reactant: CCC(C=O)=CC[C@H]1CC=C(C)C1(C)C
Agent: O=C(O)c1ccccc1
Product: CCC(=CC[C@H]1CC=C(C)C1(C)C)CO
Temperature: 100 °C

Procedure:
(R)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal (as a 95/5 E/Z isomers mixture) (412 g, 2 mol.), benzoic acid (2.44 g, 0.02 mol., 1 mol.%) and (ethylenediamine)[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]ruthenium(bispivalate) (37.6 mg, 0.04 mmol, 0.002 mol.%) were loaded altogether in a 1 L autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with 98.5% selectivity as a 95/5 E/Z isomers mixture and no loss of optical purity. Upon complete reaction conversion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars). After flash distillation, (R)-2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-en-1-ol was obtained in 97.5% yield.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([OH:13])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[SH:26]>>[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[SH:26])=[O:13]
Reactant: Cc1ccc(N)c(S)c1
Reactant: O=C(O)c1c(Br)sc2c1CCCC2
Solvent: O=S(Cl)Cl
Product: Cc1ccc(NC(=O)c2c(Br)sc3c2CCCC3)c(S)c1

Procedure:
In the same manner as in Starting Material Synthesis Example 60 and using 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, thionyl chloride and 2-amino-5-methylthiophenol, 2-bromo-4,5,6,7-tetrahydro-N-(2-mercapto-4-methylphenyl)-benzo[b]thiophene-3-carboxamide is obtained.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][C:8](OC)=[O:9])=[N+]=[N-].[H][H]>CO.[Pd]>[O:9]=[C:8]1[NH:1][CH2:4][C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COC(=O)CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC(=O)NC1
Yield: 99.3 %

Procedure:
Methyl (4S)-5-azido-4-[(tert-butoxy)carbonylamino]pentanoate (3.9 mmol, 1.07 g) was dissolved in methanol (10 mL), and 10% palladium on carbon (0.1 g) was added. The reaction was stirred overnight under 1 atm of hydrogen. The reaction was filtered and the solvent was removed in vacuo to yield the title compound (0.83 g, 99% yield). ES-MS: 215 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]C)=[O:14])=[CH:7][C:6]2=[O:17].[OH-].[Na+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7][C:6]2=[O:17]
Reactant: COC(=O)c1cc(=O)c2cc(C(F)(F)F)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2cc(C(F)(F)F)ccc2[nH]1
Yield: 44.3 %

Procedure:
Treatment of methyl 6-trifluromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.5 g. Example 19a) with sodium hydroxide (0.295 g), as described in Example 1c, gave 6-trifluoromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.21 g), m.p. 287°-289° C., δ (360 MHz, DMSO-d6) 6.72 (1H, s, 3-H), 8.01 (1H, dd, 7-H), 8.14 (1H, d, 8-H), 8.33 (1H, s, 5-H). (Found: C, 49.11; H. 2.79; N, 5.12%; C11H6NO3. 0.75H2O requires C, 48.81; H, 2.79; N, 5.17%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:47][C:48]1([CH3:55])[O:52][CH:51]([CH2:53][OH:54])[CH2:50][O:49]1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:47][C:48]1([CH3:55])[O:52][CH:51]([CH2:53][O:54][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][C:9]=3[N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:4]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:3]=2)[CH2:50][O:49]1
Reactant: CC1(C)OCC(CO)O1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OCC3COC(C)(C)O3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 120 °C
Reaction time: 75 h
Yield: 56.3 %

Procedure:
A mixture of tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.218 mmol, see Example 5), Cu(I)I (0.0416 g, 0.218 mmol), 1,10-phenanthroline (0.0393 g, 0.218 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.812 mL, 6.55 mmol) and KF on Al2O3 (40%; 0.222 g, 1.53 mmol) in toluene (4 mL) was stirred at 120° C. for 75 hours. Ethyl acetate (10 mL) was then added, and the reaction was filtered through a pad of celite. The filtrate was then concentrated to dryness. The resulting residue was purified by chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.068 g, 56%) as a solid. MS APCI (+) m/z 554.4 detected.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2]N.Cl.[C:8](=[NH:23])([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[O:16]([C:8]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[N:23][NH:2][C:1]([O:5][CH3:6])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)NN
Agent: Cl
Solvent: O
Product: COC(=O)NN=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 4 h

Procedure:
4.31 g (46.9 mmol) of methyl carbazate were initially charged in water (40 ml) and admixed with 4.75 g (46.9 mmol) of conc. hydrochloric acid (36% strength). 10.0 g (46.9 mmol) of diphenyl imidocarbonate (preparation of diphenyl imidocarbonate similar to the method of Heydayatullah, M. Bull Soc. Chim Fr. 1967, 416) were added a little at a time to this solution, at 7° C. After 4 hours of stirring with ice-bath cooling, the mixture was extracted with ethyl acetate (4×100 ml). The combined organic phases were dried over magnesium sulphate and, after filtration, concentrated under reduced pressure. The residue was dried under reduced pressure at 25° C. This gave 7.62 g of crude product containing phenol and methyl N′-diphenoxymethylenehydrazinecarboxylate in a ratio of 10:1. The yield of methyl N′-diphenoxymethylene-hydrazinecarboxylate was 693 mg (5%).
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)=[C:9]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[S:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:16]2[CH2:20][CH2:19][N:18]([C:34]([C:32]3[S:33][C:29]([CH3:28])=[CH:30][CH:31]=3)=[O:35])[CH2:17]2)=[CH:26][N:25]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)nc3c2ncn3C2CCNC2)cn1
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(n3cnc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)C2)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 5-(2-morpholin-4-yl-9-pyrrolidin-3-yl-9H-purin-6-yl)-pyrimidin-2-ylamine (37 mg, 0.08 mmol) in DMF was added 5-methyl-thiophene-2-carboxylic acid (15 mg, 0.104 mmol, 1.3 eq), EDC (20 mg, 0.104 mmol, 1.3 eq), HOBt (14 mg, 0.104 mmol, 1.3 eq) and diisopropylethylamine (32 μL, 0.184 mmol, 2.3 eq). The mixture was stirred at 50° C. for 16 hrs. Then NaHCO3 was added and the mixture extracted twice with ethyl acetate. The combined organic layers were further washed with brine before drying over Na2SO4. The crude product was purified by chromatography to afford the title compound as yellow solid (14.4 mg).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([NH:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)[CH3:20])[C:15]([CH3:38])=[N:14]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([NH:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=3)[CH3:20])[C:15]([CH3:38])=[N:14]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 55.1 %

Procedure:
1M aqueous sodium hydroxide (460 μL, 0.46 mmol) was added to a solution of 4-methoxycarbonyl-3-nitrobenzoic N′-(1-(1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide (45.5 mg, 0.092 mmol) in methanol (1.5 mL) and the mixture was stirred at room temperature for 7 hours. After adding 1 M hydrochloric acid (460 μL, 0.46 mmol), the precipitate was filtered to give the title compound (24.3 mg, 55%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:1][C:2]1[C:3]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[N:7][C:6]=2[N:20]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(C)cccc3C)c(N)nc2n1
Product: CCN(CC)CCCNc1ncc2cc(-c3c(C)cccc3C)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
Prepared as described in Example 21, starting from 0.50 g of 7-amino-6-(2,6-dimethylphenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 114 and 0.17 mL of tert-butyl isocyanate. The product was purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 95% of 0.1% trifluoroacetic acid in water/5% of 0.1% trifluoroacetic acid in acetonitrile to 65% of 0.1% trifluoroacetic acid in water/35% of 0.1% trifluoroacetic acid in acetonitrile, mp 86-91° C.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[CH:7]=1.[O-:21][Mn](=O)(=O)=O.[K+].C(O)(C)C>CC(C)=O>[C:11]1([N:10]2[C:6]([C:2]([OH:1])=[O:21])=[CH:7][C:8]([C:17]([F:20])([F:19])[F:18])=[N:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Intermediate 6 (2.84 g, 10.2 mmol) was dissolved in acetone (120 ml) and KMnO4 (11.2 gms, 71.45 mmol in 135 ml water) solution was added to it. This mixture was heated at 60° C. for 3 h and then cooled to rt. Then isopropyl alcohol was added to the reaction mixture and stirred at rt overnight. The reaction mixture filtered through celite and filtrate was evaporated on high vacuum. The residue was dissolved in 1N NaOH and washed with petether. Aqueous layer was acidified with 2N HCl solution to obtain the solid. Solid was filtered and dried on high vacuum to obtain the title compound (2.3 g) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.57-7.42 (m, 5H), 7.30 (s, 1H).