Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH2:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(O)C.I.CS[C:26]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)=[NH:27]>C(OCC)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][NH:19][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CN1CCCC1CCn1ccc2cc(CN)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN1CCCC1CCn1ccc2cc(CNC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.6 %

Procedure:
Compound 36 (124 mg, 0.482 mmol) and anhydrous ethanol (10 mL) were charged to a dry argon purged flask fitted with magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (178.5 mg, 0.626 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 96 hours. The solution was diluted with diethyl ether (50 mL) resulting in the formation of an off-white precipitate which was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 1:9) to afford a pale yellow residue 37 (100 mg, 56.6%); 1H NMR (DMSO-d6) δ 7.60 (d, 1H, J=3.8 Hz), 7.51 (m, 2H), 7.39-7.34 (2×m, 2H), 7.16-7.13 (m, 1H), 7.06 (dd, 1H, J=3.8, 5.1 Hz), 6.86-6.54 (brs, 2H), 6.37 (d, 1H, J=3.0 Hz), 4.38 (s, 2H), 4.16 (t, 2H, J=7.3 Hz), 2.94-2.87 (m, 1H), 2.16 (s, 3H), 2.11-1.92 (2×m, 3H), 1.89-1.80 (m, 1H), 1.69-1.55 (m, 3H), 1.48-1.36 (m, 1H); ESI-MS (m/z, %): 367 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([Mg]Br)[CH3:16].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1nnc(-c2ccc(F)cc2)s1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1nnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde (0.2 g, 0.961 g mmol) in THF (8 mL) was added ethyl magnesium bromide in diethyl ether (3.0 M; 0.96 mL, 2.88 mmol) at 0° C., the reaction mixture was allowed to warm to room temperature and the mixture then stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and water (15 mL), extracted with ethyl acetate (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol as yellow solid (0.1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.0-8.03 (m, 1H), 7.39-7.35 (m, 2H), 6.36 (d, 1H), 4.92-4.89 (m, 1H), 1.89-1.78 (m, 2H), 0.95 (t, 3H); LC-MS m/z calculated for [M+H]+ 239.06. found 239.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[CH:7]1[CH2:8][CH2:9][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1noc(C2CCC3(CC2)OCCO3)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)noc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of ethyl 4-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazole-3-carboxylate (558 mg, 1.889 mmol) in THF (5 mL), 2M NaOH (aq) (4.179 ml, 8.36 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The resulting mixture was poured into water (20 mL) and the pH adjusted to pH 5-6 by the addition of 1M HCl. The aqueous was extracted with EtOAc (30 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[O:15]>>[OH:15][CH:14]([CH:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C=O
Reactant: CCC(=O)c1ccc(OC)cc1
Product: CCOC(=O)C(O)C(C)C(=O)c1ccc(OC)cc1
Temperature: 135 °C

Procedure:
A mixture of 82 g of 4-methoxypropiophenone and 76.6 g of ethyl glyoxylate is heated at 135° C. for 15 hours.
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=O)[CH3:15])[C:11](=O)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][NH2:19]>C(O)C>[C:1]([O:9][C:10]1[C:14]([CH3:15])=[N:19][N:18]([CH3:17])[C:11]=1[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Reactant: CNN
Solvent: CCO
Product: Cc1nn(C)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g, 375.0 mmol) and ethanol (1.5 L) was added. To this solution was added methylhydrazine (39.90 ml, 750.1 mmol) in ethanol (150 mL). The reaction was stirred at ambient temperature for 2 hours and concentrated in vacuo to afford 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:33])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][CH2:31]O>C(#N)C>[CH3:22][C:23]1([CH3:33])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][CH2:31][Br:20]
Reactant: CC1(C)[C@H]2CC[C@@H](CCO)[C@@H]1C2
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC1(C)[C@H]2CC[C@@H](CCBr)[C@@H]1C2
Temperature: 0 °C

Procedure:
15.6 g triphenylphosphine were dissolved in 300 ml acetonitrile, and 3.02 ml bromine were added to the solution in drops with vigorous stirring at a temperature of 0° C. Then a solution of 10 g cisdihydronopol (=2-((1S,2S,5S)6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethanol) in 100 ml acetonitrile was added, and the reaction mixture was heated to 100° C. (bath temperature) for 5 hours. The reaction mixture was worked up by distilling off the solvent under reduced pressure, and the residue was purified chromatographically over silica gel using dichloromethane as eluent. 12.0 g 2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethyl bromide were obtained.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.Cl>>[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:13][C:2](=[O:3])[S:4][N:14]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: O=C(Cl)SCl
Agent: Cl
Product: COc1ccc(-c2nsc(=O)o2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
Chlorocarbonyl sulphenyl chloride (13.2 g, 0.10 mol) is added dropwise to a stirred solution of 4-methoxybenzamide (13.8 g, 0.091 mol) under dry nitrogen at room temperature. When the addition is complete, the mixture is refluxed for 8 hours, during which time hydrogen chloride gas is evolved. The solution is allowed to cool to room temperature and the solvent is removed in vacuo. The residue is triturated with methyl tert.-butyl ether and the crystalline solid is filtered off and dried, to give 5-(4-methoxyphenyl)-[1,3,4]oxathiazolin-2-one (12.2 g, 64%) as colourless crystals, m.p. 117°-118° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1)[CH3:11]>N1C=CC=CC=1>[C:1]([N:17]1[CH:13]([O:12][CH2:10][CH3:11])[CH2:14][CH2:15][C:16]1=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC1CCC(=O)N1
Solvent: c1ccncc1
Product: CCOC1CCC(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
12 g of benzoyl chloride is added to a solution of 11 g of 5-ethoxy pyrrolidin-2-one in 64 cm3 of pyridine cooled to -5° C., with agitation for 8 hours at 0° C. After 16 hours at rest, agitation is resumed for 8 hours at ambient temperature followed by dilution with 500 cm3 of water and extraction with chloroform. The solvent is then evaporated and the residue is chromatographed on silica (eluent: benzene-ethyl acetate 5-2). Then the solvent is evaporated and the residue is distilled under 0.5 mm Hg. The product obtained is washed with an aqueous solution of sodium bicarbonate, extracted with chloroform, then the solvent is evaporated. 2.1 g of expected product is obtained. m.p. =53°-55° C., isolated from petroleum ether. The sample for analysis was distilled at 130°-135° C. under 0.5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: COc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (41 mg, 31%), MS (ISP) m/z=401.6 [(M+H)+], mp 142° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine (intermediate L) (0.1 g, 0.33 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.39 mmol).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[CH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH3:26]>C(O)C.C(O)(=O)C>[CH3:5][O:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH3:26]
Reactant: CON=CCCCn1c(C)nc2c(N)nc3ccccc3c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CONCCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Sodium cyanoborohydride (16.0 g, 254 mmol) was added to a solution of 4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal O-methyloxime (prepared as described in Example 45, 15.1 g, 50.8 mmol) in ethanol (100 mL) and acetic acid (15 mL). The reaction mixture was stirred at room temperature for 2 hours, additional acetic acid (15 mL) was added, and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to provide 12.1 g of 1-[4-(methoxyamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[Cl:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH2:37][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C=O)cc1OCCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)cc1OCCCCl
Temperature: 70 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (13.7 g) and 3-(3-chloropropoxy)-4-ethoxybenzaldehyde (15.3 g) were suspended in tetrahydrofuran (150 mL), and the mixture was stirred at 70° C. for 20 hours. To the stirred reaction mixture was added sodium triacetoxyborohydride (21.7 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (16.8 g).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]([CH3:13])([CH3:12])/[C:8](=[N:10]/[OH:11])/[NH2:9])=[O:5])[CH3:3].[CH3:15]C(O)=O>>[CH3:3][C:2]([S:4]([NH:6][C:7]([CH:8]1[N:9]=[CH:15][O:11][NH:10]1)([CH3:13])[CH3:12])=[O:5])([CH3:14])[CH3:1]
Reactant: CC(C)(NS(=O)C(C)(C)C)/C(N)=N/O
Reactant: CC(=O)O
Product: CC(C)(NS(=O)C(C)(C)C)C1N=CON1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
(Z)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (140 mg, 0.633 mmol) in AcOH (4 ml) was treated with [diethoxy(2H)methoxy]ethane (0.106 ml, 0.633 mmol) at rt. The reaction was allowed to stir at rt for 16 h. LCMS showed a major peak with the expected M+H. The reaction was concentrated to dryness azeotroping with toluene 3×. The resulting oil was purified on silica gel (Biotage, EtOAc/hexanes gradient (Rf ˜0.2 in 70% EtOAc/Hex, visualized with permanganate stain), to give the expected product (27 mg, 0.12 mmol, 18% yield) consistent by LCMS. LC-MS retention time: 1.47 min; m/z (MH+): 233. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 2: Preparation of the titled compound: 2-[(2H)-1,2,4-oxadiazol-3-yl]propan-2-amine hydrochloride HCl (1.0 mL, 1.9 mmol) (2 M in Et2O) was added to a stirring solution of 2-methyl-N-{2-[(2H)-1,2,4-oxadiazol-3-yl]propan-2-yl}propane-2-sulfinamide (27 mg, 0.12 mmol) in MeOH (1 mL) at rt. The reaction was allowed to stir for 2 h and then concentrated azeotroping with toluene to give the expected product (15 mg, 0.091 mmol, 78% yield) consistent by NMR. 1H NMR (400 MHz, METHANOL-d4) δ 1.77 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[CH3:24])[CH2:7][CH2:6]1.[CH:28]1[C:33]2[NH:34][CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:28]1[C:33]2[N:34]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][CH2:12][C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[CH3:27])[CH2:10][CH2:9]4)=[O:25])=[C:16]([CH3:24])[CH:17]=3)=[O:21])[CH2:35][CH2:36][CH2:37][O:38][C:32]=2[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(C(=O)O)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Reactant: c1ccc2c(c1)NCCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCOc3ccccc32)ccc1CCCC(=O)N1CCN(CCC(C)(C)C)CC1
Yield: 10 %

Procedure:
WSCD (58 mg, 0.30 mmol) and DMAP (18 mg, 0.15 mmol) were added to a solution of 4-{4-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-4-oxo-butyl}-3-methyl-benzoic acid from Example E43 (55 mg, 0.15 mmol) and 6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (44 mg, 0.30 mmol) in di-chloromethane (3 ml) and DIEA (0.052 ml, 0.30 mmol). The mixture was heated at reflux for 5 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (6 mg, 10%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[C:14]1([S:20]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([Cl:11])[C:10]=3[C:2]([Br:1])=[CH:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a slurry of the product from Method K (4.1 g/0.018 mol) in DMF (15 mL) and cooled to 0° C. was added 1.0 g (0.025 mol) of 60% sodium hydride in mineral oil and the resulting mixture stirred at 0° C. for 15 minutes. Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, the reaction mixture warmed to room temperature and stirred for 2 hours. Water was then added (15 mL) and the resulting solid removed by filtration and dried in vacuo affording 5.9 grams (89%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]([CH2:44][C:45](O)=[O:46])#[N:43]>ClCCl>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:45](=[O:46])[CH2:44][C:42]#[N:43])[CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (580 mg, 1.50 mmol, 1.00 equiv), carbonyldiimidazole (365 mg, 2.25 mmol, 1.50 equiv) and 2-cyanoacetic acid (190 mg, 2.24 mmol, 1.49 equiv) in dichloromethane (100 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 3×100 mL of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 380 mg (56%) of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[O:22][CH:23]=1>CC(C)=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[O:22][CH:23]=[C:19]([CH2:18][N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[CH3:12])[N:20]=2)=[CH:25][CH:26]=1
Reactant: ClCCCBr
Reactant: CC1CCCN1Cc1coc(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1CCCN1Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A mixture of 1-bromo-3-chloropropane (0.7 mmol, 2 eq, 11.5 mg), potassium carbonate (0.7 mmol, 2 eq, 98 mg) and 4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl}phenol ax65 (0.35 mmol, 1 eq, 91.5 mg) in acetone (1.25 ml) is stirred at 56° C. overnight. The mixture is then filtered, washed with acetone (2×500 μl), and the solvent is removed under reduced pressure. The residue is dissolved in 3.5 ml of dichloromethane and washed twice with water (2×3.5 ml) and finally with brine (3.5 ml). The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude product is used directly in the next step.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][OH:12])=[O:8])(=[O:4])=[O:3].C(Cl)Cl.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][O:12][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:8])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccccc1C(=O)OCCO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCCOC(=O)c1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
To a slurry of 12.25 g of 2-aminosulfonylbenzoic acid, 2-hydroxyethyl ester, 125 ml of dry methylene chloride, and 7.7 ml of triethylamine was added dropwise over 10 minutes 6.3 ml of trimethylsilyl chloride (exotherm to 36° C.). The resulting solution was allowed to stand at ambient temperature for 18 hours and then washed with saturated sodium chloride solution, dried (MgSO4), and the solvent removed under reduced pressure to give an oil which was chromatographed on silica gel eluting with 25% EtOAc:hexane to give a colorless oil which slowly crystallized. Trituration with hexane gave 8.0 g of white crystals, m.p. 72°-76° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:24]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:25]([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 70 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a solution of 6-nitro-2,3,4,9-tetrahydro-1H-carbazole (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 mmol) in DMF (8 mL) was added 1-bromo-2-methylpropane (0.314 mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 9-isobutyl-6-nitro-2,3,4,9-tetrahydro-1H-carbazole (296 mg, 1.087 mmol, 94%) as a yellow powder.