Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.C1COCC1>[CH3:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:2]1[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
[3-(2-Methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (0.050 g, 0.17 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide solution (0.370 mL, 0.37 mmol, 1.0M in hexanes) was added. After 5 minutes iodomethane (11 μL, 0.18 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was stirred for an additional 5 minutes then submitted to aqueous workup. Purification by preparatory HPLC (10-100% ACN in H2O) provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:38])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:38])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[N:3]=2)[N:6]=1)=[O:29]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (400 mg, 0.967 mmol) in tetrahydrofuran (10 mL) were added dropwise 2,2,2-trichloroethyl chlorocarbonate (159 μL, 1.16 mmol) and triethylamine (202 μL, 1.45 mmol), and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether and water to give the title compound (436 mg, 76%) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:23]3[N:24]=[N:25][NH:26][N:27]=3)([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:33](=O)([O-])[O-].[K+].[K+].CI.C(OC(C)C)(C)C>CN(C=O)C.C(O)(C)C.O>[F:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:23]3[N:27]=[N:26][N:25]([CH3:33])[N:24]=3)([CH3:22])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CI
Solvent: CC(C)O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of 245 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(2H-tetrazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 5 ml of DMF were added 200 mg of potassium carbonate and 50 μl of methyl iodide, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained crude product were added isopropyl alcohol and diisopropyl ether, and the insoluble materials were collected by filtration and dried under reduced pressure to obtain 73 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(2-methyl-2H-tetrazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Ex7a). Further, to the other crude product was added diisopropyl ether, and the insoluble materials were collected by filtration and dried under reduced pressure to obtain 27 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Ex7b).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13](=[O:36])[C:14]4[C:15]([O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:16]([C:20]3[C:21]([CH3:27])=N[N:23]([CH3:26])[C:24]=3C)[N:17]=[CH:18][CH:19]=4)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:37]>O1CCOCC1>[ClH:37].[NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13](=[O:36])[C:14]4[C:15]([O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:16]([C:20]3[CH:24]=[N:23][CH:26]=[CH:27][CH:21]=3)[N:17]=[CH:18][CH:19]=4)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nn(C)c(C)c1-c1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)nccc4c3=O)cc2)CCC1
Yield: 70 %

Procedure:
Following the procedure used to prepare 3-(4-(1-aminocyclobutyl)phenyl)-2-phenyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4H-pyrano[2,3-c]pyridin-4-one, tert-butyl 1-(4-(4-oxo-2-phenyl-8-(pyridin-3-yl)-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl carbamate was reacted with HCl in dioxane to give the title compound as the HCl salt (12 mg, 70%). 1H NMR (500 MHz, CD3OD): δ 9.49 (bs, 1H), 9.25-9.20 (m, 1H), 8.90-8.85 (m, 1H), 8.78 (m, 1H), 8.25-8.20 (m, 2H), 8.15 (m, 1H), 7.91-7.80 (m, 2H), 7.41-7.20 (m, 6H), 2.71-2.62 (m, 2H), 2.55-2.45 (m, 2H), 2.20-2.14 (m, 1H), 1.88-1.82 (m, 1H). LCMS (Method I): RT=4.06 min, [M+2]+=447.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)=[CH:30][CH:29]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccccc2CBr)cc1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2CSCCO)cc1

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g, 18.1 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (2.83 g, 36.2 mmol, 2 eq.) and potassium carbonate (7.50 g, 54.3 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil
Reaction SMILES: CO[N:3]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[NH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(OC)cc1)c1ccccc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of syn-and anti-isomers of 2-(4-methoxyphenyl)-1-phenyl-1-ethanone-O-methyl oxime (10. 1.65 g, 6.46 mmol) in THF (40 ml, freshly distilled from sodium benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran solution (21.2 ml, 21.2 mmol, 1.0M solution, Aldrich) at room temperature. The resulting pale yellow solution was refluxed overnight, and cooled in an ice water bath. Water (50 ml) was carefully added to quench, followed by 20% NaOH (50 ml). The resulting colorless bi-phasic mixture was refluxed with vigorous magnetic stirring overnight, and allowed to cool to room temperature. Hexanes (40 ml) were added, and the layers separated. The aqueous portion was extracted with hexanes (1×40 ml). The combined organic portions were dried over potassium carbonate, and concentrated in vacuo to afford a colorless, slightly cloudy syrup. This syrup was purified by column chromatography on neutral alumina (I, 15 g) using an elution gradient of chloroform to 10% methanol/chloroform. The amine 15 was isolated as 1.263 g of a clear, colorless syrup (86% yield): Rf 0.20 (5% methanol/chloroform); IR (CDCl3) 3376 (w), 3316 (w), 3068 (w), 3031 (w), 3007 (w), 2965 (m), 2940 (m), 2910 (m), 2834 (m), 1614 (m), 1584 (m), 1514 (s), 1493 (m), 1466 (m), 1454 (m), 1441 (m), 1300 (m), 1245 (s), 1179 (m), 1106 (w), 1033 (m); 1H NMR (CDCl3) δ7.40-7.24 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.18 (dd, J=8.6, 4.9 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J=13.5, 4.9 Hz, 1H), 2.79 (dd, J=13.5, 8.7), 1.49 (s, 2H). Low resolution mass spec. 228(M+1, 26), 211(49), 121(44), 107(69), 106(100), 79(100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:31]=[O:32])[CH:38]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2cccc(C=O)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and (3-formylphenyl)boronic acid (189 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (270 mg, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6](C)=[C:7]([CH:10]=1)C#N.C(Cl)Cl.[CH3:18][C:19]([OH:21])=[O:20]>O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]([CH3:7])=[C:18]([CH:10]=1)[C:19]([OH:21])=[O:20]
Reactant: COc1cc(C#N)c(C)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 91 %

Procedure:
A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2.0 g, 10.4 mmol) in AcOH (20 mL), water (20 mL) and conc. sulfuric acid (20 mL) was heated to 120° C. for 10 h. Water (100 mL) and DCM (100 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (2.0 g, 91%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]−=210 at 3.37 min. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1>>[S:11]1[C:12]2[C:7](=[CH:6][C:5]([CH:3]([OH:4])[CH2:2][N:24]3[CH2:23][CH2:22][CH:21]([N:20]4[C:19]5[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=5[NH:17][C:16]4=[O:15])[CH2:26][CH2:25]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)c1ccc2c(c1)CCCS2
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc3c(c2)CCCS3)CC1
Yield: 38 %

Procedure:
By the procedure of Example 29, and starting from 6-(alpha-bromoacetyl)-thiochromane and 4-(2-oxo-1-benzimidazolinyl)-piperidine, the corresponding aminoketone is obtained in 38% yield (MG 16413), m.p. 184°-186° C., which is then reduced with NaBH4.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[P:7]([OH:10])([OH:9])[OH:8].[ClH:11]>>[ClH:11].[CH3:2][N:1]([O:8][P:7]([CH2:3][C:4]([OH:6])=[O:5])([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: OP(O)O
Reactant: CNCC(=O)O
Agent: Cl
Product: CN(CC(=O)O)OP(=O)(O)CC(=O)O

Procedure:
In a like manner to Example 1, a solution of sarcosine (8.9 parts by weight), orthophosphorous acid (8.2 parts by weight) in 100 parts by weight of 18% hydrochloric acid is reacted to give, on evaporation, 25.8 parts by weight of 2-(N-methyl-N-carboxymethylamino)phosphonoacetic acid hydrochloride as a pale yellow amorphous solid having a 31P-nmr signal at 13.3 ppm downfield from H3PO4 in water (JP-CH =18H3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[CH:22][C:21]=1[C:31]#[N:32].CCOC(C)=O>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31]([NH2:32])=[C:21]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20]3=[N:19][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-ethanone (300 mg, 0.99 mmol) in dichloroethane (3 mL) is stirred at room temperature while TiCl4 (311 mg, 1.64 mmol) is added dropwise. After the addition, the mixture is stirred at room temperature for 5 minutes and a solution of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (150 mg, 0.815 mmol) in dichloroethane (3 mL) is added dropwise. After the addition, the mixture is heated to 125° C. for 5 hours. After cooling, the mixture is poured into a mixture of ice cold saturated aqueous NaHCOs solution (30 mL) and EtOAc (30 mL). The resultant precipitate is filtered through celite and washed with EtOAc (2×10 mL). The filtrate is extracted by EtOAc (3×15 mL). The organic layers are combined and washed with brine and dried (MgSO4). After filtering off the drying agent, the filtrate is concentrated and purified by column chromatography (silica gel, 0%˜40% EtOAc/hexane) to provide the titled compound 5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine as light yellow solid:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10]1[N:11]([CH2:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:13]=2
Reactant: BrCC1CCOCC1
Reactant: CCCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To a solution of 8-methoxy-N2-pentyl-9H-purine-2,6-diamine trifluoroacetic acid salt (223 mg) in dry DMF (3.85 mL) was added potassium carbonate (339 mg) at 60° C. and the mixture was stirred for 90 mins. The mixture was cooled to room temperature and 4-(bromomethyl)tetrahydro-2H-pyran (121 mg) was added in one portion. The reaction was stirred at 50° C. overnight and was then cooled and taken up in EtOAc (20 mL). The organics were washed with water (2×10 mL), separated, dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to afford the title compound as an off-white solid (140 mg).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:28]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)=O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:28](/[C:20]1[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:30]1[O:31][C:32]([CH3:35])=[N:33][N:34]=1)[CH3:16]
Reactant: Cc1nnc(C(=O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/c1cc(Br)cc(C(F)(F)F)c1)c1nnc(C)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of NaH (60%, 1.13 g, 28.35 mmol) in dry THF (20 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (6.49 g, 28.35 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-trifluoromethyl-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone (9.047 g, 27 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9 g of the desired product (Yield: 90%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8].C(N(CC)CC)C.C(#N)C>>[CH2:6]([N:9]([C:2]([O:4][CH3:5])=[O:3])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8]
Reactant: C=CCNc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)OC)c1ccc(C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (34 μL, 0.00044 mol) was added to a mixture of tert-butyl 1-[4-(allylamino)phenyl]cyclopropanecarboxylate (6.0×10−1 mg, 0.00022 mol) and triethylamine (92 μL, 0.00066 mol) in acetonitrile (1.0 mL, 0.019 mol) at rt. The reaction mixture was stirred at rt for 30 minutes, then was washed with water, and then extracted with EtOAc (3×). The organic layers were combined and concentrated. To the residue was added 4.0M HCl in dioxane and the reaction was stirred at rt for 2 h. The solvent was removed in-vacuo and used in the following step. LC/MS: 276.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[C:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH:20]=2)[CH2:4][N:3]=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[S:1]1[CH:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH2:4][N:3]=[CH:2]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C4CN=CS4)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(C4CN=CS4)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a mixture of 0.54 gm (1.8 mMol) 5-(4,5-dihydrothia-zol-5-yl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 20 mL trifluoroacetic acid were added slowly 320 μL (2 mMol) triethylsilane. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residual oil was partitioned between ethyl acetate and aqueous potassium carbonate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from acetonitrile to provide 0.40 gm (74%) of the title compound compound as a crystalline solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[C:10]1([CH2:16][CH2:17][C:18]([O:20]C)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:20])[CH2:17][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNOC
Reactant: COC(=O)CCc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)); to a slurry of N,O-dimethylhydroxylamine hydrochloride (4.91 g, 50.4 mmol, 2.1 eq.) in toluene (50 ml) at −10° C. was added AlMe3 (2 M in hexanes, 25.2 ml, 50.4 mmol, 2.1 eq.) dropwise. After addition, the mixture was allowed to warm to r.t. and stirred for 1 h. The mixture was cooled to −5° C. and a solution of methyl 3-phenylpropanoate 82 (3.94 g, 24.0 mmol, 1 eq.) in toluene (40 ml) was added dropwise. The reaction mixture was then allowed to warm slowly to r.t. and stirred for 3 h. The solution was cooled to 0° C. and quenched carefully by dropwise addition of HCl and the reaction mixture was extracted with EtOAc (4×70 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/EtOAc (80:20 to 75:25), giving the Weinreb amide 83 as a clear, colourless oil (4.45 g, 97%). Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006); Murphy, J. A. et al., Org. Lett. 7, 1427-1429 (2005)).
Reaction SMILES: C(O[CH:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]23[CH2:33][CH:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=42)[C:25]2[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)(=O)C.C([O-])=O.[NH4+]>[Pd].CO>[CH:21]1[C:20]2[C:19]3([CH2:18][N:15]4[CH2:14][CH2:13][CH:12]([CH2:5][C:6]5[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=5)[CH2:17][CH2:16]4)[CH2:33][CH:26]([C:27]4[C:32]3=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC(c1cccnc1)C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1cncc(CC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 1-[1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl]-1-(3-pyridyl)methanol acetate, prepared as in Example 53, (175 mg, 0.40 mmol), ammonium formate (175 mg, 2.78 mmol), and 10% palladium on carbon (175 mg) were heated to reflux in methanol (6 mL) under nitrogen (g) for 8 h. Additional ammonium formate (175 mg, 2.78 mmol) was added and heating was continued for an additional 8 h. The suspension was filtered through celite and the solids were washed thoroughly with methanol and ethyl acetate. Concentration of the filtrate left an off white foam. Flash chromatography on silica using 3% methanol/dichloromethane gave the title compound as a colorless glass (100 mg, 0.26 mmol, 66%). This was dissolved in methanolic hydrogen chloride and concentrated from methanol (3×100 mL) to give the hydrochloride salt, mp 183°-185° C.