Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cccc2ncc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cnc2cccc([N+](=O)[O-])c2c1
Reaction time: 2 h

Procedure:
3-Hydroxy-5-nitroquinoline, as described above in Step D, (2.86 g, 15.04 mmol), tert-butyldimethylsilyl chloride (2.95 g, 19.55 mmol) and imidazole (3.07 g, 45.12 mmol) were dissolved in DMF (20 mL) and stirred for 2 hours. The reaction mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17](Cl)=[O:18])(=[O:11])=[O:10])[O:4][N:3]=1.[C:23]([CH2:25][C:26]1[C:27]([CH3:35])=[C:28]([C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])[NH2:29])#[N:24].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([CH2:25][C:26]1[C:27]([CH3:35])=[C:28]([NH:29][C:17]([C:13]2[S:14][CH:15]=[CH:16][C:12]=2[S:9]([N:8]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:6]=2[CH3:7])[CH2:20][O:21][CH3:22])(=[O:11])=[O:10])=[O:18])[C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])#[N:24]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Cl
Reactant: Cc1cc(C)c(CC#N)c(C)c1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(CC#N)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a solution of 3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarbonyl chloride (0.49 g, 1.34 mmol) in dichloromethane (4 mL) was added 3-cyanomethyl-2,4,6-trimethylaniline (0.24 g, 1.34 mmol) at 0° C. Triethylamine (0.21 mL, 1.47 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 2 hours, then mixed with water (10 mL). The organic material was separated, and the aqueous layer was extracted with dichloromethane (2×5 mL). The extracts were combined and washed with water (10 mL) and saturated sodium chloride (10 mL), dried (MgSO4), then concentrated. The residue was purified by flash chromatography (SiO2, hexane: ethyl acetate/3:1, then 1:1) to give N2-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.28 g, 41%) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[B][B][B][B][B][B][B][B][B][B]>CO>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccccc1F
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of 4-formylbenzoic acid 47a (3.33 mmol, 500 mg), 2-fluoroaniline 47b (3.33 mmol, 370 mg), and decaborane (1 mmol, 122 mg) in 8 mL of MeOH was stirred at room temperature for 15 min. The mixture was concentrated and purified by preparative reverse-phase chromatography to afford 0.81 g (99%) of 47c.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]=3[C:24]=2[CH3:25])=O)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][C:9]2[C:10]([CH3:27])=[C:11]([CH3:26])[C:12]3[O:16][C:15]([CH3:17])=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]=3[C:24]=2[CH3:25])=[CH:28][CH:29]=1
Reactant: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccccc1
Solvent: CO
Product: Cc1oc2c(C)c(C)c(NCc3ccc(F)cc3)c(C)c2c1-c1ccccc1
Yield: 56 %

Procedure:
By using 4-fluoro-N-(2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-yl)benzamide, the title compound was synthesized according to Example 2b. Yield: 56%. Melting point: 135-136° C. (Methanol)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[O:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>O1CCCC1>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:22])[CH2:20][CH3:21])=[C:10]2[C:6]=1[CH:7]=[CH:8][O:9]2
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(O)c2occc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccc(C)c2ccoc12

Procedure:
To a stirred mixture of 7-hydroxy-4-methylcoumarone (88.0 g, 0.5 mole), triethylamine (83.4 mL, 0.6 mole) and tetrahydrofuran (1 L) was added propanoyl chloride (46.27 g 0.5 mole) dropwise. The mixture was poured into cold 0.5 N hydrochloric acid (3 L) slowly with stirring. The solid was collected, washed with water, and dried. mp. 147° C.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:23]=[CH:22][C:12]2[O:13][C:14]3[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=3[O:16][C:11]=2[CH:10]=1.N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C1C[O:40][CH2:39][CH2:38]1>>[C:30]([NH:21][C:19]1[CH:18]=[CH:17][C:15]2[O:16][C:11]3[CH:10]=[C:9]([NH:8][C:39](=[O:40])[CH3:38])[CH:23]=[CH:22][C:12]=3[O:13][C:14]=2[CH:20]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)Oc1ccc(N)cc1O2
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)Oc1ccc(NC(C)=O)cc1O2
Yield: 82 %

Procedure:
To a mixture of 900 ml of toluene and 900 ml of THF were added 50.0 g (0.233 mole) of 2,7-diaminodibenzodioxin and 55.3 g (0.699 mole) of pyridine and to the resulting mixture was added 59.5 g (0.583 mole) of acetic anhydride in drops over a period of 10 minutes at room temperature with stirring. After the dropwise addition, the mixture was stirred overnight and a precipitate was recovered by filtration. The precipitate was reslurried with toluene (250 mix 2) and dried under reduced pressure to give 57.0 g (0.191 mole, 82.0% yield) of 2,7-bis(acetylamino)dibenzodioxin. The product showed a purity of 99.3 area % (HPLC, 254 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:39][CH:40]([N-]C(C)C)C.C1COCC1.ICC.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([N:31]1[CH2:35][CH2:34][CH:33]([CH2:39][CH3:40])[C:32]1=[O:36])[CH2:17][CH2:16][C@@:15]35[OH:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCCN1[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1CCN([C@H]2CC[C@@]3(O)[C@H]4Cc5ccc(OCc6ccccc6)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)C1=O
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In 5 mL of THF, 248 mg (0.50 mmol) of 1-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl)-pyrrolidin-2-one obtained in Example 36-1 was dissolved, and 4.1 mL (1.48 mmol) of 0.36N LDA/THF solution was added at 0° C., followed by stirring the mixture for 1 hour. Thereafter, 0.08 mL (0.99 mmol) of iodoethane was added thereto and the resulting mixture was stirred for 3 hours. Aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 176 mg (yield: 67%) of the captioned compound.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)#[N:2].BrC1C=C(NC(=NC#N)[O-])C=CC=1.[CH3:36][C:37]1[C:45]2[C:44]([N:46]3[CH2:51][CH2:50][NH:49][C@@H:48]([CH3:52])[CH2:47]3)=[N:43][CH:42]=[N:41][C:40]=2[NH:39][CH:38]=1.C(N(CC)CC)C>C(O)(C)C>[C:1]([N:3]=[C:4]([N:49]1[CH2:50][CH2:51][N:46]([C:44]2[C:45]3[C:37]([CH3:36])=[CH:38][NH:39][C:40]=3[N:41]=[CH:42][N:43]=2)[CH2:47][C@@H:48]1[CH3:52])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)#[N:2]
Reactant: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Agent: N#CN=C([O-])Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(C(F)(F)F)c4)[C@@H](C)C3)c12
Temperature: 140 °C

Procedure:
Phenyl N′-cyano-N-(3-(trifluoromethyl)phenyl)carbamimidate, prepared analogously to N-3-bromophenyl-N′-cyanocarbamimidate from Example 5, step A (36 mg, 0.12 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B, (35 mg, 0.15 mmol), and triethylamine (0.05 ml, 0.36 mmol) were combined in isopropanol in a microwave vessel. The reaction was heated at 140° C. for 30 min. under microwave conditions. The solvent was evaporated, and the residue was washed with CH2Cl2 (3×10 ml). The crude product was purified by Prep-HPLC to afford (S)—N′-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)-piperazine-1-carboximidamide as white solid.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[N:45][CH:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:47][C:46]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[N:45][CH:44]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1cnc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (30 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (4.8 mg, 0.04 mmol), HOBt (26 mg, 0.19 mmol), EDC (76 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.63 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((5-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (36 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the reaction mixture was stirred overnight at rt. The solvents were removed under reduced pressure. Purification of the residue by preparative HPLC gave the title compound as a yellow oil. TLC: rf (4:6 hept-EA)=0.31. LC-MS-conditions 07: tR=0.85 min, [M+H]+=397.40.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][NH:20][CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:25][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:18]=[C:17]3[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]3=[N:15][C:14]=2[N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:25][CH2:24]2)[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (144 mg, 0.272 mmol) in DCM (2.72 mL) at 0° C. was treated with pyridine (66.0 μL, 0.816 mmol), followed by acetic anhydride (51.3 μL, 0.544 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure and taken up in MeOH, filtered through a 0.45 μm Millipore® syringe filter, and purified via HPLC Method A to give the title compound, as a TFA salt, as a yellow solid (74.9 mg, 48.2%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.82 (m, 2H), 1.97 (m, 2H), 2.11 (m, 4H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.45 (m, 2H), 2.73 (t, J=5.9 Hz, 0.7H), 2.84 (t, J=5.9 Hz, 1.3H), 3.11 (m, 2H), 3.47 (m, 2H), 3.81 (t, J=5.9 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H), 4.40 (m, 1H), 4.49 (m, 1H), 4.59 (s, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.97 (ddd, J=11.2, 8.5, 3.2 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 458.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[CH:20][S:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)C=Cc1ccccc1Cl
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
2-Aminobenzene sulfonamide (153 mg, 0.89 mmol) was added in one portion to a solution of 2-(2-chloro-phenyl)-ethenesulfonyl chloride (150 mg, 0.63 mmol) in pyridine (2 mL) at RT. After 30 minutes of stirring, no more starting material was detected by tlc. The reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and a small amount of methanol. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, dried over MgSO4, and concentrated under reduced pressure. Purification by preparative tlc afforded the target compound, which was then recrystallized from ethyl acetate/pentane/diethyl ether to afford the title compound (85 mg, 36%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:5][CH:2]([OH:1])[CH2:3]4)=[O:7])[CH2:9]3)[O:26][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.5 mg (0.295 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 46 mg (34% of theory).
Reaction SMILES: [H-].[Na+].CC([Si](C)(C)[O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)(C)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+]>O1CCCC1.CO.C(Cl)Cl>[CH:27]([O:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10][C@@H:9]1[OH:8])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
350 mg (8 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 1.426 g (4 mmol) of 3'-O-[(1,1-dimethylethyl)dimethylsilyl]thymidine [Can. J. Chem., 56, 2768 (1978)] in 8 ml of tetrahydrofuran under an atmosphere of argon, and the resulting mixture was stirred at 60° C. for 2 hours and then allowed to cool to room temperature. A solution of 988 mg (4 mmol) of benzyl bromide in 2 ml of tetrahydrofuran was then added dropwise to the mixture, followed by 300 mg (2 mmol) of sodium iodide. The reaction mixture was then stirred at room temperature for 17 hours, after which it was freed from the solvent by distillation under reduced pressure. The concentrate was dissolved in 50 ml of ethyl acetate, and the resulting solution was washed twice each time with 50 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 4 ml of tetrahydrofuran, and 4 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride were added to the solution. The resulting mixture was then stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 60 g of silica gel (230-400 mesh) using a gradient elution method, with methylene chloride containing from 1 to 2.5% by volume methanol as the eluent, to give 377.7 mg (yield 23%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:4]=1[O:14][CH2:15][CH2:16][O:17][CH3:18].[C-:19]#[N:20].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:4]1[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:19]#[N:20]
Reactant: COCCOc1cccc(CCl)c1OCCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cccc(CC#N)c1OCCOC
Temperature: 70 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
A mixture of 1-(chloromethyl)-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (1.15 g, 4.19 mmol) and potassium cyanide (0.82 g, 12.56 mmol) in DMF (10 mL) was stirred at 70° C. for 17 h. After cooling to rt, ethyl acetate (100 mL) was added, and the mixture was washed with sat. sodium bicarbonate (30 mL), 5% aqueous LiCl (2×30 mL), and brine (30 mL), dried with sodium sulfate, and concentrated. Column chromatography on silica (2:1 hexanes/ethyl acetate) afforded (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.94 g, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.02 (m, 2H), 6.88 (dd, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.84 (s, 2H), 3.75 (m, 2H), 3.63 (m, 2H), 3.43 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH2:28]1[O:30][C@@H:29]1[CH2:31][OH:32]>>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:28][C@H:29]([OH:30])[CH2:31][OH:32])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: OC[C@@H]1CO1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(C[C@H](O)CO)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a solution of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol) was added (R)-(+)-glycidol (0.05 M in isopropanol, 2.8 mL, 0.00014 mol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at 80° C. for three hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ammonium hydroxide/methanol/dichloromethane (2:7:91) followed by ammonium hydroxide/methanol/dichloromethane (2:10:88) as mobile phase to yield (2S)-3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}propane-1,2-diol (0.023 g, 0.000053 mol).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:16]=1[C:22]([OH:24])=O.[NH2:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1>O1CCCC1>[CH3:13][O:14][C:15]1[C:19]([CH3:20])=[C:18]([CH3:21])[S:17][C:16]=1[C:22]([NH:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)=[O:24]
Reactant: COc1c(C(=O)O)sc(C)c1C
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(C(=O)Nc2nnn[nH]2)sc(C)c1C
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
1,1'-Carbonyldiimidazole (4.1 g, 25 mmoles) is added to a solution of 3-methoxy-4,5-dimethyl-2-thiophenecarboxylic acid (4.5 g, 24 mmoles) in tetrahydrofuran (80 mL) under argon. The mixture is stirred and heated under reflux for 1.5 hours. 5-Aminotetrazole (2.0 g, 24 mmoles) is added and heating under reflux is continued for an additional 2.5 hours. The mixture is cooled, and the precipitate is filtered off, rinsed with tetrahydrofuran, dried, and stirred in 2N HCl. After 10 minutes the suspended solid is collected by filtration, rinsed with water and dried to afford the product (4.4 g); mp 229° C. (dec).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:28])=[C:16]([C:19]5[O:23][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:21][N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.O1CCOCC1.[OH-].[Na+]>[Cl-].[Na+].O>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:28])=[C:16]([C:19]5[O:23][C:22]([NH:24][CH:25]([CH3:26])[CH3:27])=[N:21][N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1nnc(-c2cc3c(-c4nccc(C5CC5)n4)c[nH]c3cc2F)o1
Temperature: 100 °C
Yield: 29 %

Procedure:
A 5 mL glass microwave tube was charged with 5-(3-(4-cyclopropylpyrimidin-2-yl)-6-fluoro-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (180 mg, 0.338 mmol) and treated with dioxane (2 mL) and 1 N NaOH (1 mL) and heated at 100° C. for 10 min in the microwave. The reaction mixture was treated with brine and extracted with EtOAc (2×20 mL), concentrated and purified by reverse phase using a Gilson automated platform (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water by volume over 10 min), then dried in a Genevac Series II Evaporator affording the title compound (48.2 mg, 0.098 mmol, 29.0% yield) as a yellow amorphous solid. LC-MS (ESI, pos. ion) m/z: 379.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93-12.03 (1H, m), 8.98 (1H, d, J=7.4 Hz), 8.59 (1H, d, J=5.1 Hz), 8.29 (1H, d, J=2.7 Hz), 7.85 (1H, d, J=7.4 Hz), 7.45 (1H, d, J=11.3 Hz), 7.21 (1H, d, J=5.3 Hz), 3.82 (1H, dq, J=13.2, 6.5 Hz), 2.13-2.22 (1H, m), 1.27 (6H, d, J=6.5 Hz), 1.20-1.25 (2H, m), 1.12-1.20 (2H, m). 19F NMR (377 MHz, DMSO-d6) δ ppm −74.90 (3F, s), −119.9 (1F, s).