Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:30])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
To a solution of (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (0.057 g, 0.14 mmol) in DMF (1.406 mL) was added HATU (0.064 g, 0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM (0.077 mL, 0.70 mmol). The resulting mixture was stirred at room temperature for 48 h after which time the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide (30 mg, 0.05 mmol 37% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=2.67-2.72 (m, 3 H), 6.77-6.90 (m, 4 H), 7.14-7.23 (m, 2 H), 7.30 (d, J=2.02 Hz, 1 H), 7.36 (d, J=15.16 Hz, 1 H), 7.44-7.51 (m, 3 H), 8.42 (d, J=3.03 Hz, 1 H), LC/MS (m/z, MH+): 419.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:11]O>Cl>[CH3:11][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccnc(C)c1

Procedure:
5 g 2-methyl-isonicotinic acid was stirred 24 h at 50° C. in 150 mL 1.3 mol/L HCl in methanol. The solvent was removed and water was added to the residue. The mixture was basified with saturated sodiumhydrogencarbonate solution and extracted with ethylacetate. The organic layer was dried with magnesiumsulfate and evaporated to give 4.5 g of the desired product.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:22]4[O:41][CH:42]=[CH:43][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Sn:53]([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[C:22]4[O:41][C:42]([Sn:53]([CH3:56])([CH3:55])[CH3:54])=[CH:43][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc([Sn](C)(C)C)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of di-tert-butyl {4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-yl}imidodicarbonate (400 mg, 0.653 mmol) in anhydrous THF (10 mL) was added lithium diisopropylamide (2 M in THF, 1.6 mL, 3.3 mmol), and the mixture stirred for 30 minutes. Chlorotrimethylstannane (1 M in THF, 3.92 mL, 3.92 mmol) was added, and the mixture warmed to RT. The mixture was then cooled to −78° C., quenched by addition of glacial acetic acid (0.2 mL), and warmed to RT. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 20% EtOAc:heptane) to afford 347 mg (69%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 0.10 (s, 6 H), 0.45 (s, 9 H), 0.92 (s, 9 H), 1.39 (s, 18 H), 1.50-1.62 (m, 2 H), 1.87-2.09 (m, 4 H), 2.24 (d, J=12.1 Hz, 2 H), 3.69-3.80 (m, 1 H), 4.21 (tt, J=11.5, 3.9 Hz, 1 H), 7.08-7.11 (m, 1 H), 7.78 (s, 1 H), 7.88-7.91 (m, 1 H), 8.31 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.C([O-])(=O)C.[Na+].Cl.[NH2:17][OH:18].C(OCC)(=O)C>CO.CCCCCC.O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(C=NO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2 L round bottom flask was set up with a mechanical stirrer, thermometer, N2 inlet and reflux condensor. A solution of 3,5-dimethyl-benzaldehyde (70 g. 522 mmol) in 300 mL of methanol was added, followed by the addition of sodium acetate (44 g, 536 mmol). Hydroxylamine-HCl (37 g, 532 mmol) was added portion-wise over 5 minutes, during which time the maximum temperature reached without cooling was 27° C. The mixture was stirred for an additional 2 hours at room temperature. TLC (10% ethyl acetate in hexane) indicated the absence of the starting aldehyde and the appearance of oxime. Most of the methanol was removed on a rotary evaporator, resulting in the formation of a precipitate. Ether and water were added to the concentrated suspension, and then the ether layer was collected, dried over MgSO4, and removed on a rotary evaporator. The white crystalline material was air-dried, resulting in 77 g (100%) of 3,5-dimethyl-benzaldehyde oxime. 1H-NMR (300 MHz, CDCl3)δ(ppm): 8.09 (s, 1H), 7.22 (s, 2H), 7.05 (s, 1H), 2.33 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:14][N:10]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[C:7](=[O:12])[O:8][C:9]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 6-methyl-1H-3,1-benzoxazine-2,4-dione (2 g), anhydrous potassium carbonate (0.64 g), dimethylformamide (10 ml) and methyl iodide (0.9 ml) was stirred at room temperature for 24 hours. More methyl iodide (0.9 ml) was added and stirring continued for a further 18 hours. More potassium carbonate (1 g) and methyl iodide (0.8 ml) were added and stirring continued for a further 23 hours. The mixture was poured on to a mixture of ice and water. The resulting precipitate was washed with water and dried to give the novel compound 1,6-dimethyl-1H-3,1-benzoxazine-2,4-dione, m.p. 165°-170°.
Reaction SMILES: C(OC1C(OC)=CC=CC=1/C=C/C1N=C2SC=CN2C(=O)C=1)C(C)C.IN1C(=O)CCC1=O.[CH:34]1([CH2:37][O:38][C:39]2[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2/[CH:47]=[CH:48]/[C:49]2[N:50]=[C:51]3[S:59][CH:58]=[CH:57][N:52]3[C:53](=[O:56])[C:54]=2[I:55])[CH2:36][CH2:35]1>C(#N)C>[I:55][C:54]1[C:53](=[O:56])[N:52]2[CH:57]=[CH:58][S:59][C:51]2=[N:50][C:49]=1/[CH:48]=[CH:47]/[C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([O:45][CH3:46])[C:39]=1[O:38][CH2:37][CH:34]([CH3:36])[CH3:35]
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)C
Agent: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C

Procedure:
A solution of Step 1 intermediate (600 mg, 1.683 mmol) was treated with N-iodosuccinimide (416 g, 1.851 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford 600 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.05 (d, J=6.9 Hz, 6H), 2.04-2.08 (m, 1H), 3.71 (d, J=6.3 Hz, 2H), 3.81 (s, 3H), 7.10-7.12 (m, 2H), 7.27-7.30 (m, 1H), 7.48-7.53 (m, 2H), 7.96 (d, J=4.8 Hz, 1H), 8.17 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 483.16 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21]C)[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N)SC=3)=NOC)C(=O)N2C=1C([O-])=O)(=O)C.[Na+].C(OCC1CS[C@@H]2C(NC(=O)C(C3N=C(N)SC=3)=NOC(C)C)C(=O)N2C=1C(O)=O)(=O)C>>[NH2:28][C:25]1[S:26][CH:27]=[C:23]([C:19](=[N:20][OH:21])[C:18]([NH:17][CH:16]2[C:15](=[O:30])[N:10]3[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][S:8][C@H:9]23)=[O:29])[N:24]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(C)C)c3csc(N)n3)[C@H]2SC1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
Gelules were prepared with 250 mg of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid or sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate or 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(1-methylethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid or the syn isomer of 7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylic acid and sufficient excipient to obtain a final weight of 400 mg.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:34])[C:25]=2[CH:35]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:34])[C:25]=3[CH:35]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CCOC(=O)c1sc2ccc(N)cc2c1C
Product: CCCCN1C(=O)C(Nc2ccc3sc(C(=O)OCC)c(C)c3c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and ethyl 5-amino-3-methyl-1-benzothiophene-2-carboxylate in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (400 MHz, d-THF): δ 8.85 (bs, 1H), 7.61 (d, 1H), 7.19 (dd, 1H), 7.17-7.13 (m, 2H), 7.09-7.01 (m, 3H), 6.97-6.95 (m, 1H), 4.35-4.28 (m, 2H), 3.76 (t, 2H), 2.34 (s, 3H), 1.89-1.80 (m, 2H), 1.54-1.44 (m, 2H), 1.35 (t, 3H), 1.01 (t, 3H); Mass Spectrum: M−H+ 498.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CN(C)[CH:34]=[O:35]>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH:34]=[O:35])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (1.6 mL, 2.6 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.38 mL, 2.7 mmol) in THF (5.5 mL) at −78° C. Upon complete addition, the reaction temperature was raised to 0° C. for 30 minutes. After re-cooling to −78° C., 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (0.50 g, 1.7 mmol, prepared as in Example 2, Step 1) in THF (2.5 mL) was added dropwise. After stirring for 1 hour at −78° C., N,N-dimethylformamide (0.26 mL, 3.4 mmol) was added. After 25 minutes, the reaction was quenched by the addition of saturated NH4Cl solution into the −78° C. mixture. After warming to room temperature, the mixture was diluted with water and extracted with EtOAc. The combined extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a white solid (0.43 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([CH2:10][CH2:11]3)[C:8]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])=[CH:4][CH:3]=1.C(=O)(O)[O-:30].[Na+:33]>O1CCOCC1.O.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:30])[CH2:11]3)[C:8]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Na+:33]
Reactant: O=C([O-])O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccc(F)cc2)SC2CCN12
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(Oc2ccc(F)cc2)SC2CC(=O)N12
Yield: 95.5 %

Procedure:
A mixture of a solution of 500 mg of 4-nitrobenzyl 3-(4-fluorophenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 101 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. Then the reaction mixture was filtered through Celite, and then lyophilised to yield 348 mg of the title compound as a pale yellow crystalline solid (95% of the theoretical yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:11][CH2:12][C:13]#[CH:14].C(N)(C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:14]#[C:13][CH2:12][CH2:11][C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(Br)n1
Reactant: C#CCCC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)(C)N
Product: CC(C)(C)OC(=O)CCC#Cc1cccc(CO)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 56.9 %

Procedure:
To a 200 mL round-bottom flask, 3.49 g of 2-bromopyridine-6-methanol, 3.0 g of t-butyl 4-pentynoate, 190 mg of BHT, 1.17 g of copper(I) iodide, 877 mg of tetrakis(triphenylphosphine)palladium(0), 2.72 g of t-butylamine and 56 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. After the DMF was removed under reduced pressure from the reaction mixture, saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate=2:1) to give 2.76 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pent-4-ynoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.[F:18][B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.F[B-](F)(F)F>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[F:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(C)=O
Product: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A mixture of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (425 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether:EtOAc=2:1) to provide desired product of 6-chloro-2-(3-fluoro-1H-indol-2-yl)pyridin-3-ol (120 mg, yield: 46.2%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=8.0 Hz, 1H), 7.39˜7.44 (m, 1H), 7.25˜7.34 (m, 1H), 6.97˜7.20 (m, 3H). MS (M+H)+: 263/265.
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][CH3:15].[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>O1CCCC1>[CH3:15][O:14][C:4]1[C:5]([CH3:13])=[C:6]([CH3:12])[C:7]([O:10][CH3:11])=[C:8]([CH3:9])[C:3]=1[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)([OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Reactant: CCCCCCC(=O)c1cccnc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(O)(c1cccnc1)c1c(C)c(OC)c(C)c(C)c1OC
Yield: 39.3 %

Procedure:
A Grignard reagent was prepared from 693 mg (28.3 g atom) of magnesium, 7.6 g (29.3 mmol) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene and tetrahydrofuran at 65° C. and cooled to 0° C., to which a solution of 3.75 g (21.9 mmol) of 3-heptanoylpyridine in 10 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, to which water was added and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified with silica gel column chromatography (isopropyl ether) and recrystallized from hexane, to give 3.2 g (39%) of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptanol. m.p. 109°-110° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:31][C:32]([CH3:34])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:32]([CH3:34])[CH3:31])[CH2:6]2)[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (49 mg, 0.10 mmol), acetone (8.28 μL, 0.113 mmol), and triethylamine (44.3 μL, 0.318 mmol) in dichloromethane (0.67 mL) was added sodium triacetoxyborohydride resin (89 mg, 0.20 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was filtered and concentrated and then purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) to give the racemic product. LCMS: found m/z=447.2 (M+H)+. The racemic mixture was separated by chiral HPLC (column IA, eluting with 5% ethanol/95% hexanes, at flow rate 18 mL/min) to give two peaks (isomer 1:9.5 mg, 21%; isomer 2: 9.2 mg, 20%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[Br:16][C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:14]=1[Br:15]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 500 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([C:5](=[O:18])[N:6]2[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:1][C@@H:2]1[C@@H:7]2[CH2:8][C@@H:4]([C:5](=[O:18])[N:6]2[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CI
Reactant: COc1ccc(CN2C(=O)[C@H]3C[C@H](O)[C@@H]2C3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@H]3C[C@H](OC)[C@@H]2C3)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of the (1S,4R,6S)-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-heptan-3-one (500 mg, 2.02 mmol) in anhydrous THF (20 mL) was added NaH (60 wt %, 4.04 mmol) at room temperature. The mixture was stirred at 40° C. for 30 min. After cooling to room temperature, CH3I (0.41 mL, 8.08 mmol) was added. The reaction mixture was stirred for 1 h at ambient temperature and quenched with water (50 mL), extracted by EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated to give (1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one. MS (ESI+): m/z 262 (M+H+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1(S([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=3)[C:30]([C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)=[CH:29]2)(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.CC(C)=O>[N+:37]([C:34]1[CH:35]=[C:36]2[C:31]([C:30]([C:40]3[CH:41]=[CH:42][C:43]([C:44]#[N:45])=[CH:46][CH:47]=3)=[CH:29][NH:28]2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: N#Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3cc([N+](=O)[O-])ccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reaction time: 8 h

Procedure:
Add 100 mL of 1 M TBAF in THF to a slurry of 4-(1-benzenesulfonyl-6-nitro-1H-indol-3-yl)-benzonitrile 8 (14.3 g, 35 mmol) in 50 mL of THF. Monitor the reaction by TLC. If starting material remains add more 1 M TBAF in THF until the reaction is complete. Pour reaction mixture into 200 mL of saturated aqueous sodium bicarbonate and then extract the resulting solution 3× with EtOAc. Combine the organic extracts and wash the extracts with saturated aqueous bicarbonate, water (2×), brine. Dry the resulting organic solution over Na2SO4, filter, and then remove the organic solvent to provide a solid. Redisolve the solid in ˜400 mL of acetone with heating and then add ˜100 mL hexanes until a precipitate forms. Let the solution cool and then collect the precipitate. Concentrate the filtrates and redisolve in ˜300 mL of 50% acetone/hexanes with heating. Let the solution cool and then place in a freezer at −20° C. overnight. Collect the crystals that form. The combined yield of the title compound is 6.71 g, 25.5 mmol, 72%. LRMS (API ES−)=262.0 (M−1).