Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([O:21]C)[C:6]2[C:7](=[O:18])[C:8]3[S:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=3[O:17][C:5]=2[CH:4]=1.N1C(=O)CC[C@H]1C(O)=O.Cl>>[OH:2][C:3]1[CH:20]=[C:19]([OH:21])[C:6]2[C:7](=[O:18])[C:8]3[S:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=3[O:17][C:5]=2[CH:4]=1
Reactant: COc1cc(OC)c2c(=O)c3sc4ccccc4c3oc2c1
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: O=c1c2sc3ccccc3c2oc2cc(O)cc(O)c12
Yield: 72 %

Procedure:
Example 29 (0.26 g, 0.83 mmol) and Pyr-HCl (5 g) were heated together at 210° C. for 30 minutes. The reaction was worked up by partitioning between EtOAc/MeOH and 2N HCl aq. The organic layer was washed with brine and dried over MgSO4. The organic layer was concentrated and the product triturated with MeOH to yield the desired pdt 31 as a tan solid (0.17 g): Mp>300° C.; 1H NMR (DMSO-d6) δ 12.49 (s, 1H), 11.09 (s, 1H), 8.22 (d, 1H, J=3.4 Hz), 8.20 (d, 1H, J=4.0 Hz), 7.76-7.61 (m, 2H), 6.61 (d, 1H, J=2.1 Hz), 6.31 (d, 1H, J=2.1 Hz); MS 283 (M−H)−.
Reaction SMILES: ClC1C=CC(SCC2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](C4C=CC=CC=4OC)[CH:18]=3)[NH:13]C(C)(C)C=2)=CC=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])[CH:40]=2)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC(S)=CC=1>>[CH3:49][O:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:51])([CH3:50])[CH:33]=[C:32]2[CH2:31][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc(Cl)cc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccc(Cl)cc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-Chlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 84 mg of 4-chloro benzenethiol reacted to give 10 mg of the title compound as a foam.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=O)=[CH:30][N:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:32]([C:31]3[CH:30]=[N:29][C:28]([OH:27])=[CH:36][CH:35]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(-c3ccc(O)nc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 50 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 6-hydroxynicotinic-acid, the title compound was obtained in 50% yield (90% purity by HPLC).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][CH2:3][CH3:4].Cl.C([N:41]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:41][C:21]([C:19]1[N:20]=[C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:24])[N:8]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:7]([CH2:29][NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:6]3[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[S:17][CH:18]=1)=[O:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(N)=O)cs3)cc12
Yield: 93.3 %

Procedure:
A solution of 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.79 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.74 g, 93.7%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([O:26]C)=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=CC(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Yield: 89.5 %

Procedure:
The same procedures as in Example 149 were carried out from the compound obtained in Example 158 (4.3 g), 1 mol/L of an aqueous sodium hydroxide solution (18 mL), and methanol (180 mL), to give the captioned compound (3.7 g, 89%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O>C(O)C.[Pd]>[N:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cnccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1N1CCCCC1
Reaction time: 15 h
Yield: 93 %

Procedure:
To a solution of 3-nitro-4-(piperidin-1-yl)pyridine (1.0 equiv.) in ethanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 4-(piperidin-1-yl)pyridin-3-amine (93%) as an oil. LCMS (m/z): 178.0 (MH+); LC Rt=1.68 min. 1H NMR (CDCl3): δ 8.01 (s, 1H), 7.96 (d, J=5.4, 1H), 6.78 (d, J=5.1, 1H), 3.64-3.74 (m, 2H), 2.86-2.94 (m, 4H), 1.66-1.78 (m, 4H), 1.58-1.64 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+:6]([O-:8])[CH:7]=1.[CH3:21][NH2:22]>CO>[C:9]1([C:5]2[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][C:2]([NH:22][CH3:21])=[CH:7][N+:6]=2[O-:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [O-][n+]1cc(Cl)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CN
Solvent: CO
Product: CNc1c[n+]([O-])c(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
To 1.00 g of 5-chloro-2,3-diphenylpyrazine 1-oxide, 20 ml of 40% methylamine in methanol was added and the mixture was-reacted in a sealed tube at room temperature for 15 hours. The reaction solution was extracted with ethyl acetate after adding water. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting crude crystal was washed with diisopropyl ether to obtain 536 mg of the desired compound as a pale yellow crystal having a melting point of 145 to 147° C.
Reaction SMILES: FC(F)(F)C1C=CC(S(Cl)(=O)=O)=CC=1.[C:15]1([C:21]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:24]=[C:23]([C:39](OCC)=[O:40])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:24]=[C:23]([CH:39]=[O:40])[CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1
Agent: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c1

Procedure:
Using 4-trifluoromethylbenzenesulfonyl chloride instead of tosyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-chloro-4-methyl-5-nitropyridine (9.419 g, 54.6 mmol) in dioxane (110 mL) was added tetrakis(triphenyl phosphine) palladium (6.330 g, 5.46 mmol) and the mixture stirred for 15 min prior to the addition of trimethyl boroxine (7.68 mL, 54.6 mmol) and potassium carbonate (22.64 g, 164.0 mmol). The reaction mixture was heated under reflux for 6 h then allowed to cool to rt over 16 h. Ethyl acetate (200 mL) was added and the mixture stirred vigorously for 1 h. The mixture was filtered through celite, washing through with ethyl acetate/THF (1:1, v/v). Brine (100 mL) was added and attempted separation of layers resulted in a thick emulsion. After removal of all volatiles, ethyl acetate (300 mL) was added and the mixture filtered, giving rise to a biphasic mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane then purified via flash column chromatography (SiO2, ethyl acetate/isohexane, 3:7, v/v) to give the title compound as an orange oil. δH (CDCl3): 2.59 (3H, s), 2.60 (3H, s), 7.12 (1H, s), 9.07 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[NH:15][C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]3=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.[CH2:19](Br)[CH3:20]>>[CH2:19]([N:15]1[C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]2=[CH:17][CH:18]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]12)[CH3:20]
Reactant: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1
Reactant: CCBr
Product: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21

Procedure:
It was found that the 2-nitro-4-(4-pyridinyl)benzoic acid prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reducing it to 2-amino-4-(4-pyridinyl)benzoic acid, (b) reacting the 2-amino-4-(4-pyridinyl)benzoic acid with phosgene to form 4-(4-pyridinyl)isatoic anhydride, (c) alkylating the 4-(4-pyridinyl)isatoic anhydride with ethyl bromide to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (d) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (e) hydrolyzing that ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[C:17]=2[I:26])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].CC1C2COC(=O)C=2C=CC=1CCN1CCNCC1>O1CCOCC1>[ClH:27].[I:26][C:17]1[C:18]2[CH2:22][O:21][C:20](=[O:23])[C:19]=2[CH:24]=[CH:25][C:16]=1[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2I)COC3=O)CC1
Agent: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCc2c1ccc(CCN1CCNCC1)c2I

Procedure:
4-Iodo-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride was prepared from tert-butyl-4-[2-(4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate using 4N HCl in dioxane in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above. LC-MS (IE, m/z): 373 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[C@@H:9]3[CH2:20][CH2:21][N:8]3[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Yield: 99.2 %

Procedure:
40.58 g (128.7 mmol) of ethyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 300 ml of ethanol and 32.5 ml (130 mmol) of 4N-sodium hydroxide solution were heated to reflux on a steam bath for 1.5 hours. The alcohol was evaporated on a rotary evaporator. The aqueous phase was washed twice with methylene chloride and acidified to pH 3-4 with 32.5 ml (130 mmol) of 4N hydrochloric acid. The suspension obtained was cooled and suction filtered. The filter residue was washed with a small amount of ice-water and dried. There were obtained 36.67 g (99%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of m.p. 159°-160°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12](=[CH2:17])[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2.[C:20]1([CH2:26][O:27][C:28](=[O:37])[NH:29][C@H:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[F:36])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.BrC1C2OCCOC=2C=C(C=O)C=1.O1C2=CN=C(CO)C=C2C=C1>CN(C)C(N(C)C)=N.CN(C=O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:17][N:33]1[CH2:34][CH2:35][C@H:30]([NH:29][C:28]([O:27][CH2:26][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:37])[C@H:31]([F:36])[CH2:32]1)[C:13]([O:15][CH3:16])=[O:14])=[N:9][C:8]([O:18][CH3:19])=[CH:7][CH:6]=2
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Reactant: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: O=Cc1cc(Br)c2c(c1)OCCO2
Agent: OCc1cc2ccoc2cn1
Solvent: CN(C)C=O
Product: COC(=O)C(CN1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1)c1c(F)cnc2ccc(OC)nc12
Temperature: 80 °C
Yield: 100 %

Procedure:
A solution of methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (953 mg, 3.63 mmol), cis-phenylmethyl[3-fluoro-4-piperidinyl]carbamate Enantiomer 2 (for a synthesis see WO2004058144, prepared by analogy to Examples 142(b), (c) and (d) from the Enantiomer 2 of Example 142(a)) (1.1 g, 4.35 mmol) and 1,1,3,3-tetramethylguanidine (6 drops) in DMF (3.5 ml) was heated at 80° C. under argon for 3 hours, cooled and evaporated. Chromatography, eluting with 1% methanol/dichloromethane, gave the product in 100% yield.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3].[OH-].[K+].Br[C:25](P(=O)(OCC)OCC)([F:27])[F:26]>C(#N)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH:25]([F:27])[F:26])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:2]=[CH2:3]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: C=CCc1c(O)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CCc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-allyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (3.6 g, 12.53 mmol) was dissolved in acetonitrile (62.6 mL) and water (62.6 mL), then KOH (14.06 g, 251 mmol) was added and the solution was stirred until all the KOH went into solution. The resulting solution was then cooled to −78° C. (solution froze) and diethyl bromodifluoromethylphosphonate (4.45 mL, 25.06 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. After 1 hour, EtOAc and water were added, and the resulting layers were separated. The aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (d, J=3.79 Hz, 1H) 7.08 (t, J=74.7 Hz, 1H) 6.96 (s, 1H) 6.76 (d, J=3.79 Hz, 1H) 5.89 (dd, J=16.93, 10.36 Hz, 1H) 4.91-5.05 (m, 2H) 3.57 (d, J=6.32 Hz, 2H) 1.59 (s, 9H). MS (ESI+) m/z 338.1 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+:2]=[N-:3].[ClH:32]>O1CCOCC1>[ClH:32].[N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)=[N+:2]=[N-:3]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1CN=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCNCC2)c1CN=[N+]=[N-]
Reaction time: 2 h

Procedure:
1,1-dimethylethyl 4-{[5-(azidomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxylate (5.14 g) is treated with a 4M solution of hydrogen chloride in dioxane (50 ml). The reaction mixture is left to stand for 2 hours. The solvent is evaporated and co-evaporated with dichloromethane (2×50 ml) then diethyl ether (2×50 ml) to give 5-(azidomethyl)-1,6-diethyl-N-4-piperidinyl-1H-pyrazolo[3,4-b]pyridin-4-amine, hydrochloride salt. This product is dissolved in dichloromethane (100 ml) and the solution is treated with DIPEA (6.3 ml) and trimethylsilyl isocyanate (1.8 ml), and then is left to stand at room temperature for 18 hours. Water (50 ml) is added and the precipitated solid is collected by filtration, washed with diethyl ether and dried to give 4-{[5-(azidomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:10])[CH2:6][C:7](O)=[O:8].[NH3:11]>>[SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:10])[CH2:6][C:7]([NH2:11])=[O:8]
Reactant: N
Reactant: O=C(O)CC(=O)NCCS
Product: NC(=O)CC(=O)NCCS
Reaction time: 1 h

Procedure:
31 g of methyl ester of N-(2-mercapto-ethyl)malonamic acid obtained in Example 3a) were added to 220 cm3 of aqueous 20% solution of aqueous ammonia, with stirring, while the temperature was kept below or equal to 30° C. Stirring was continued for 1 hour at ambient temperature. A slight cloudiness was removed by filtration on sintered glass. The filtrate was evaporated to dryness at reduced pressure. The solid obtained was recrystallized from ethyl acetate. After filtering and drying in vacuum at 50° C., 27 g of N-(2-mercaptoethyl)malonamide were obtained in the form of a white solid with a melting point of 100° C.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]([NH:38][C:11](=[O:12])[CH:10]([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[CH:35]([OH:37])[CH2:36]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)C(CS(=O)(=O)Cc2ccccc2)NC(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1 g, 2.8 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 3.46 mmol) prepared as in Reference 1, EDC (1.5 g, 7.8 mmol), and HOBt (1.5 g, 9.6 mmol) were combined. Dichloromethane (10 mL) was added and then 4-methylmorpholine (1.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried with MgSO4 and evaporated under vacuum. 3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 1.94 mmol) was obtained as yellowish foam and was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (6 mL) was added and the mixture was stirred at ambient temperature for 1 hour. Evaporation under vacuum gave crude morpholine-4-carboxylic acid [1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as TFA salt, which was used without further purification.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[N:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:29][CH:30]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1ccc(Br)cn1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(Br)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-bromo-2-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 10): tR=1.92 min; Mass spectrum (ESI+): m/z=467/469 (Br) [m+H]+.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45]>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[C:37]([F:36])([F:50])[F:49])=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 95%).