Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CC(C)CCBr
Agent: Cl
Product: CC(C)CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 1-bromo-3-methylbutane (0.359 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.45 g) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:3]=12
Reactant: O=[N+]([O-])O
Reactant: COCCOc1cnc2[nH]ccc2c1F
Product: COCCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Reaction time: 0.25 h
Yield: 67 %

Procedure:
4-Fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 2.09 mmol) was added to HNO3 fuming (4 mL) at 0-5° C., and the reaction was stirred for 15 minutes. Ice was added, and the resulting solid was filtered and dried to yield 4-fluoro-5-(2-methoxyethoxy)-3-nitro-1H-pyrrolo[2,3-b]pyridine (360 mg, 67% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2].[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzenamine (3.00 g, 14.9 mmol, 1.0 equiv) in CH2Cl2 (90 mL) at 25° C., was added 3-chloro-2,2-dimethylpropanoyl chloride (3.9 mL, 29.8 mmol, 2.0 equiv) followed by triethylamine (4.2 mL, 29.8 mmol, 2.0 equiv). The solution was heated to 40° C. After 48 h, the solution was washed with water (50 mL), and brine (50 mL). After concentration in vacuo, the residue was purified by silica gel chromatography (1:10 hexanes:EtOAc to 1:5 hexanes:EtOAc) to afford 3-chloro-2,2-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)propanamide. MS—No (MH+) observed.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[ClH:31].[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:32][CH:33]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: NCCCSc1ccncc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.48 ml (4.96 mmol) of 4-t-butylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.20 g of the desired compound (free base) (88.0%, yellow powder).
Reaction SMILES: CC(C)=O.[OH-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:19]2[CH2:21][CH2:20]2)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([CH:19]2[CH2:21][CH2:20]2)[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)[C@@H](c1ccc(Cl)cc1)C1CC1
Yield: 0 %

Procedure:
Horse liver esterase (4.6 g horse liver acetone powder, Sigma Chemical Co.) is suspended in water (200 ml) at room temperature and the pH is adjusted to 7.5 with 1.0 M sodium hydroxide. Methyl (2RS)-(4-chlorophenyl)(cyclopropyl)ethanoate (7.0 g, 31.4 mol) is added and stirring is continued at room temperature with the addition of 1.0 M sodium hydroxide as needed to maintain the pH at 7.1-8.0. After 14 ml of base had been consumed, the pH was brought to 3 with 10% hydrochloric acid, ethyl acetate is added and the mixture is filtered through diatomaceous earth. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography affords (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (2.5 g, 37.9%) and recovered ester (4.1 g). The ester was resubjected to the hydrolysis conditions with additional horse liver esterase (1.0 g ) for an extended period during which an additional 4.4 ml of 1.0 M sodium hydroxide is consumed. Acidification, workup and purification as described above affords methyl (2S)-(4-chlorophenyl)(cyclopropyl)ethanoate (3.1 g, 36.2%) The enantiomeric excess of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (as the methyl ester) and (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid are determined with the chiral NMR shift reagent Eu(hfc)3 to be >96:4 and >98:2 respectively.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(OCC)(=O)C>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
To a solution of 2,5-dichloropyridine (2 g) in dimethylformamide (30 mL) was added potassium carbonate (3.73 g) and piperazine (1.16 g) and the mixture was stirred at 110° C. for 4 hours. After cooling the reaction mixture, thereto was added ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, solvent: chloroform/methanol=100/0 to 99/1) to obtain 5-chloro-2-(1-piperazinyl)pyridine (0.28 g, Yield: 10%) as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)=[CH:11][CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:12]3[S:13][C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:10][CH:11]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CN4CCCC4)s3)nc12
Temperature: 60 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6μL, 0.07 mmol) was added and the reaction was heated to 60° C. for 4 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([O:42][CH2:43][CH3:44])[CH:36]=1.[O:46]1[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]1>C1COCC1>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[C:39]([O:52][CH:49]2[CH2:50][CH2:51][O:46][CH2:47][CH2:48]2)[CH:38]=[C:37]([O:42][CH2:43][CH3:44])[CH:36]=1
Reactant: CCOc1cc(O)cc(C(=O)OC)c1
Reactant: OC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(OC2CCOCC2)cc(C(=O)OC)c1
Reaction time: 6 h
Yield: 56 %

Procedure:
To a mixture of triphenylphosphine (1.18 g, 4.49 mmol, 1.1 equiv) and DEAD (0.76 mL, 0.85 g, 4.89 mmol, 1.2 equiv) in anhydrous THF (10 mL) was added 3-ethoxy-5-hydroxy-benzoic acid methyl ester (0.8 g, 4.08 mmol, 1.0 equiv; prepared as described in WO 99/05123 A1, Astra Pharmaceuticals Ltd.) and tetrahydro-pyran-4-ol (0.42 g, 4.08 mmol, 1.0 equiv), dissolved in THF (10 mL), at 0° C. under Ar. After stirring for 6 h, the solvent was partially removed by evaporation under reduced pressure, water (50 mL) added and the reaction mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material yielding 0.64 g (56%) of the title compound which was directly used in the next step. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J=7.0 Hz, 3H), 1.67-1.72 (m, 2H), 1.91-1.97 (m, 2H), 3.48-3.53 (m, 2H), 3.81 (s, 3H), 3.85-3.91 (m, 2H), 3.96 (q, J=7.0 Hz, 2H), 4.40-4.44 (m, 1H), 6.56-6.58 (m, 1H), 7.08-7.10 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 14.59, 31.68, 51.99, 63.69, 64.89, 71.86, 107.82, 108.06, 109.09, 131.98, 158.17, 160.05, 166.61. MS (ISP): 281.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:10])#[N:2].[OH:30]S(O)(=O)=O>>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:7]2[S:6][N:5]=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[C:3]=2[C:1]([NH2:2])=[O:30])=[O:10])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 45 °C
Yield: 100 %

Procedure:
A mixture of 1-(4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)-3-(3-morpholinopropyl)urea (113 mg, 0.27 mmol) in 3.5 mL conc. H2SO4 was heated at 45° C. After 1.5 hours the reaction was quenched into 100 mL ice water giving a white gel-like solid. The aqueous solution was made basic using Na2CO3 and then extracted with EtOAc, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated giving the title compound as a light beige solid (118 mg, 100%).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:26]=[N:25][CH:24]=[CH:23][C:9]=1[C:10]([CH:12]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11].O>CN1C(=O)CCC1>[OH:11][C:10]1[C:9]2[CH:23]=[CH:24][N:25]=[CH:26][C:8]=2[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C(=O)c1ccncc1F)C(=O)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1=C(O)c2ccncc2C(C)(C)C1=O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of potassium t-butoxide (0.34 g, 3.0 mmol) in 8 mL NMP stirred at room temperature was treated with a solution of ethyl 2-(3-fluoroisonicotinoyl)-4-methyl-3-oxopentanoate (0.28 g, 1.00 mmol) in 1 mL NMP drop wise. The dark red solution was stirred at room temperature for 15 hours, M+1=262. There were two spots that had the MS=262. The mixture was poured into 200 mL water. The mixture was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (20 mL), dried, and concentrated. The crude product was purified by column eluting with 10-50% EtOAc/hexane to give 0.2 g oil. MS m/e: (M+H)+ 262.
Reaction SMILES: [CH2:1]([S:9](Cl)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:13][C@:14]([CH3:50])([CH2:48][OH:49])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([S:9]([O:49][CH2:48][C@:14]([OH:13])([CH3:50])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: CCCCCCCCS(=O)(=O)Cl
Product: CCCCCCCCS(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting octanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C33H50N4O10S2 m/z: 727 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[CH:5]=O.[NH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:21]=1[C:22]([NH2:24])=[O:23].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:24][C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([O:29][CH3:30])=[CH:26][C:25]=3[O:31][CH3:32])[N:19]=2)[CH:7]=[C:8]([CH3:18])[C:9]=1[O:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1
Reactant: Cc1cc(C=O)cc(C)c1OC[C@@H]1CCC(=O)N1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC[C@@H]4CCC(=O)N4)c(C)c3)nc2c1
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A mixture of (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (0.200 g, 0.81 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.81 mmol), NaHSO3 (0.093 g, 0.89 mmol), and p-TsOH (0.015 g, 0.08 mmol) in DMA (10 mL) was heated at 150° C. for 48 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (2×200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound as an off-white solid (0.108 g, 31%). 1H NMR (300 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.79-7.91 (m, 3H), 6.74 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.88-3.94 (m, 4H), 3.84 (s, 3H), 3.63-3.75 (m, 2H), 2.30 (s, 6H), 2.09-2.27 (m, 3H), 1.91-2.00 (m, 1H). APCI MS m/z 424 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.C([O:12][CH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][N:15]=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>ClCCl>[N+:23]([C:20]1[CH:21]=[C:22]2[C:14]([CH2:13][OH:12])=[N:15][NH:16][C:17]2=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cnc2[nH]nc(COCc3ccccc3)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2[nH]nc(CO)c2c1
Reaction time: 1 h
Yield: 87.3 %

Procedure:
BBr3 (7.4 mL, 7.4 mmol, 1M in heptane) was added to a solution of 3-(benzyloxymethyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.70 g, 2.46 mmol) in dichloromethane (25 mL) at −78° C., and the reaction mixture was stirred at this temperature for 1 hour. Saturated aqueous NaHCO3 was added, followed by addition of ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford (5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (417 mg, 87%), as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH:17]=[CH2:18]>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:18][CH:17]=[CH2:16])[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCBr
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (20.0 g), lithium hydride (1.57 g), and dimethylformamide (800 ml) was stirred for 3 hrs at 25° C., under nitrogen. 3-Bromopropene (15.5 g) was added and the mixture was stirred for an additional eighteen hrs. The redaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 15.7 g (63%) of 5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]1[C:34](=[NH:36])[NH2:35]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][N:27]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CC1=CC(C(=N)N)N(O)C=C1
Product: CCc1ccc(C2CC(c3nc(-c4cc(C)ccn4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-4-methylpyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 35 mg (38% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:10][C:9]=2[O:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)n1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48 e, using 6-(4-chloro-phenyl)-5-cyclobutoxy-pyrazin-2-ylamine (example 50c) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 97.4%, 381.1096 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][CH:15]=1)=[O:12])[CH2:3]2
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In accordance with the general method, 60 mg (0.17 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4-bromophenyl)acetamide hydrochloride, 23.3 mg (0.17 mmol) of 4-fluorophenylboronic acid, 0.17 ml of 2M sodium carbonate solution and 6.1 mg (0.01 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of dimethylformamide. 32 mg (51% of theory) of the title compound are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH3:23])=[C:8]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[C:17]([O:19][CH:20]([F:22])[F:21])[CH:16]=[N:15][C:14]=23)[CH:9]=1)=[O:4].[OH-].[K+].CO.Cl>C1COCC1>[F:22][CH:20]([F:21])[O:19][C:17]1[CH:16]=[N:15][C:14]2[N:13]([N:12]=[CH:11][C:10]=2[C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=2[CH3:23])[CH:18]=1
Reactant: COC(=O)c1cc(-c2cnn3cc(OC(F)F)cnc23)c(C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(C(=O)O)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 40 °C
Yield: 64.8 %

Procedure:
Methyl-4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylate (0.916 g, 2.70 mmol) was dissolved in THF (4 mL). 1 M KOH in MeOH (12.0 mL, 12.0 mmol) was added and the reaction heated to 40° C. for 16 h. After the hydrolysis was complete, treated with 1N HCl and the resulting solids were filtered, washed with water and dried to afford the title compound (0.568 g, 1.75 mmol). LRMS (APCI) calc'd for (C13H9F2N3O3S) [M+H]+, 326.0; found 326.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C([NH2:22])C1C=CC=CC=1.CS(O)(=O)=O>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)O
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in scheme 14) can be treated with a benzylic amine, such as benzylamine, to displace the chloro moiety. Hydrogenation under standard conditions in the presence of an acid (e.g., methanesulfonic acid) can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the 2,5-diamino-benzenesulfonamide intermediate as a salt. Alternatively, the 2,5-diamino-benzenesulfonamide salt can be prepared by reduction of the 2-amino-5-nitro-benzenesulfonamide (prepared as described in schemes 14 and 15) under standard hydrogenation conditions in the presence of an acid (e.g., methanesulfonic acid). Subsequent reaction with methanesulfonyl chloride affords the desired 2-amino-5-methanesulfonylamino-benzenesulfonamide intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].Cl.[CH2:12]([O:14][NH2:15])[CH3:13].Cl>N1C=CC=CC=1.O1CCCC1>[CH2:12]([O:14][NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])[CH3:13]
Reactant: CCON
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCONC(=O)c1cc(Br)c(Br)s1
Reaction time: 0.5 h

Procedure:
At room temperature, 6.8 g of 4.5-dibromothiophene-2-carboxylic chloride is stirred, in portions, into 6.8 g of O-ethylhydroxylamine hydrochloride in 10 ml of pyridine and 80 ml of tetrahydrofuran. After 30 minutes, dilute hydrochloric acid was added, and the product was filtered off and washed with water. Yield: 5.8 g; m.p.: 117-119° C.