Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)=[CH:33][C:32]=2[CH3:46])=[C:28]([CH:47]([CH3:49])[CH3:48])[NH:27][N:26]=1)(=O)C.[NH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53].[I-].[Na+]>C(#N)C.C(O)C>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53])=[CH:33][C:32]=3[CH3:46])=[C:28]([CH:47]([CH3:48])[CH3:49])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: Cc1cc(OCCCNC(C)(C)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (1 g) in dichloromethane (16 mL) were added triethylamine (0.29 mL) and methanesulfonyl chloride (0.15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (1.12 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (2 mL) and ethanol (2 mL). To the solution were added 2-amino-2-methyl-1-propanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.16 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].[CH3:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20]>>[CH2:1]([S:13][CH2:20][CH:19]([CH3:21])[C:18]([O:17][CH3:16])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCCCCCCS
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCSCC(C)C(=O)OC
Temperature: 122 °C
Reaction time: 0.17 h

Procedure:
Into the same type equipment used in Example 1 202 grams of 98% 1-dodecanthiol was added to 1.0 grams of KOH and 112 grams methylmethacrylate with stirring over a 10 minute period. The reaction mixture went from 70° C. to 98° C. The reaction mixture was stirred an extra hour at 98° C. to 93° C. and slowly heated up to 122° C. over a 5 hour period. The reaction mixture was stripped at 125° C. and 20 mm pressure. GC analysis indicated a purity of 93.2% product. 300 grams filtered product was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(C)(C)C.Cl.[CH3:32][P:33]1(=[O:44])[O:38][CH2:37][C:36]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][O:34]1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:41]2[CH2:42][CH2:43][C:36]3([CH2:35][O:34][P:33]([CH3:32])(=[O:44])[O:38][CH2:37]3)[CH2:39][CH2:40]2)=[CH:25][CH:26]=1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CP1(=O)OCC2(CCN(Cc3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2-(4-Bromomethyl-benzoylamino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester (150 mg, 0.31 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (89 mg, 0.37 mmol), and DIEA (107 μL, 0.62 mmol) were combined in DMF (4 mL) and stirred at room temperature for 18 h. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography of the crude (0-10% MeOH/CH2Cl2) afforded the desired product as a colorless solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The crude was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The residue was triturated with EtOAc and filtered to afford the desired product as a colorless solid 1H NMR (DMSO-d6, 600 MHz) δ 9.69 (s, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.5 Hz, 1H), 7.02 (t, J=4.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.13 (s, 2H), 4.16-4.04 (m, 4H), 3.54 (s, 2H), 2.43-2.37 (m, 2H), 2.34-2.28 (m, 2H), 1.68-1.62 (m, 2H), 1.52 (d, J=17.0 Hz, 3H), 1.42-1.38 (m, 2H). MS: cal'd 512 (MH+), exp 512 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2.45 g (6.8 mmol) 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 5 ml CH2Cl2 were treated with 4 ml TFA at 0° C. The solution was stirred at RT for 0.5 h, and at 40° C. for 1 h. The solution was concentrated and the residue was dissolved in ether and water. 2M NaOH was added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4 to yield 1.65 g (94%) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 259 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.F[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=1.Cl>CN(C=O)C>[CH3:13][C:11]1[NH:10][N:9]=[C:8]([O:7][C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH3:21])[CH:20]=2)[CH:12]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)n[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
Potassium carbonate (2.23 g, 16.1 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (3.16 g, 32.2 mmol) and 5-fluoro-2-nitrotoluene (5.00 g, 32.2 mmol) in DMF (50 ml), and the mixture was stirred at 70° C. for 3 hours. After completion of the reaction, a reaction mixture was poured into 2N hydrochloric acid (50 ml) and extracted with ethyl acetate (30 ml×2). An organic layer was washed with water (50 ml×3), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellowish solid of 5-methyl-3-(4-nitro-3-methylphenyloxy)pyrazole (2.51 g, yield: 27.8%). mp: 114-117° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (d, J=0.5 Hz, 3H), 2.61 (s, 3H), 5.72 (d, J=0.5 Hz, 1H), 6.98-7.04 (m, 2H), 8.05 (d, J=9.8 Hz, 1H), 10.12 (br s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])([O-:15])=[O:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 3.00 gm (0.019 mole) of 2-quinolinecarboxaldehyde, 3.44 gm (0.019 mole) of m-nitrobenzhydrazide and 100 ml of ethanol is refluxed for 9 hrs. The hot solution is filtered and cooled slowly to room temperature. The mixture is chilled. The crystals which separate are collected. The crude product is recrystallized from tetrahydrofuran to yield 3.04 gm (50%) of the title compound, having a melting point of 217°-218° C.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][N:3]=[N:2]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH:1]1[C:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)COCCc1cnn[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COCCc1cnn[nH]1

Procedure:
Stir a mixture of tert-butyl 2-[2-(1H-triazol-5-yl)ethoxy]acetate (14.15 g; 62.26 mmol) and trifluoroacetic acid (70.75 mL, 935.69 mmol) in dichloromethane (70.75 mL) for 2 hours at room temperature. Concentrate the reaction mixture under reduced pressure to provide the title compound containing additional trifluoroacetic acid (20.22 g, >100%) as a brown solid. MS (m/z): 172.05 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[NH2:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[N:8]1[N:5]2[CH:6]=[CH:7][C:2]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:3][C:4]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Clc1ccn2nccc2n1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2nccc2n1
Yield: 96 %

Procedure:
The commercially available 5-chloropyrazolo[1,5-a]pyrimidine is reacted with (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate under the amine displacement conditions described in example 5.6.5 to give 96% product.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH:13]=1>C(OCC)(=O)C.O>[NH2:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[C:12]([C:6]3[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[O:16][N:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)on2)c1
Temperature: 25 °C

Procedure:
Tin (II) chloride (135 mg, 0.6 mmol) was added to a solution of 5-(2,6-dichlorophenyl)-3-(3-nitrophenyl)isoxazole compound (100 mg, 0.3 mmnol) in ethyl acetate (20 mL). The resulting solution was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was concentrated under reduced pressure to give the title compound as an off-white solid, 71 mg.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([C@@H:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH3:17])[CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C@@H:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=2)[CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of benzaldehyde (0.1 mL, 1 mmol) and N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (248 mg, 1 mmol) in dichloroethane (5 mL) was added sodium triacetoxyborohydride (300 mg, 1.4 mmol) in one portion and the mixture was stirred at room temperature for 16 hours. After this time a solution of saturated aqueous sodium hydrogen carbonate (20 mL) was added and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate (2×20 mL) and the extracts washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give N-{(1S)-1-[3-(benzylamino)phenyl]ethyl}-6-chloropyrazin-2-amine (330 mg, 97%) as an off white solid of reasonable purity.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[N:2]1.[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH3:21][N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]nnc2c1C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(nnn2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of dimethyl 1H-benzotriazole-4,5-dicarboxylate (10.1 g, 43 mmol) in dimethylformamide is treated portion-wise, with cooling, with sodium hydride. When gas evolution has ceased, the reaction mixture is treated dropwise with iodomethane (6.7 g, 461 mmol) stirred at room temperature for 2 hours, concentrated in vacuo and diluted with a mixture of chloroform and water. The layers are separated; the organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 35% ethyl acetate in hexanes to give the title product as a white solid, 3.15 g, mp 146°-147° C. The structure is determined by NMR NOE experiments.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][O:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[C:47]=1[O:48][CH2:49][CH:50]=O.[ClH:58]>C1C=CC=CC=1>[ClH:58].[CH3:44][O:45][C:46]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[C:47]=1[O:48][CH2:49][CH2:50][NH:1][CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc2c(OCCN=[N+]=[N-])cccc2c1=O
Reactant: COc1cccc(OC)c1OCC=O
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1cccc(OC)c1OCCNCCOc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reaction time: 18 h
Yield: 40 %

Procedure:
A mixture of 4.5 g of Intermediate XII, 3.7 g of triphenyl phosphine and 2.85 g of 2,6-dimethoxyphenoxy-acetaldehyde (prepared as per Nelson, W. L. et al., J. Med. Chem. 22: 1125, 1979) in 45 ml of benzene was stirred at 20°-25° C. for 18 hours and at reflux for 5 hours. The solvent was evaporated off in vacuo and the residue was dissolved in 80 ml of anhydrous methanol containing 3Å molecular sieves at 0° C. The mixture was stood for 1 hour at 0° C. and for 1 hour at 20°-25° C., and then poured into iced water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (49:1). The base obtained was treated with ethanolic hydrogen chloride. After crystallization from ethanol, the title compound was obtained. Yield 40%, m.p. 200-°202° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2sccc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2sccc2c1Cl
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A mixture of ethyl 4-chlorothieno[2,3-b]pyridine-5-carboxylate (800 mg, 3.31 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] in 15 mL of ethanol and 5 mL of 2.5 N sodium hydroxide is heated at reflux for 90 minutes. The mixture is cooled to 0° C. and the pH is adjusted to 4 by the addition of 2 N hydrochloric acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration and washed with water to provide 250 mg of 4-chlorothieno[2,3-b]pyridine-5-carboxylic acid as a white solid, mp 172-174° C.; 1H NMR (DMSO-d6) δ 7.62 (d, J=6 Hz, 1H), 8.14 (d, J=6 Hz, 1H), 8.94 (s, 1H); MS 212.0 (M−H)−.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:24](Br)(C)C>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH:22]([CH3:24])[CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Reactant: CC(C)Br
Product: CC(C)n1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Yield: 62 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with isopropylbromide (10.2 g, 83 mmol) in 62% yield (6.44 g) as a white solid: mp 114.5-116° C.; MS EI m/e 324 (M+)
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]=3[CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)[CH3:6])C.CO>[OH-].[Na+].Cl.C(OCC)(=O)C>[CH:19]1[C:20]2[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][C:18]=1/[C:16](/[CH3:17])=[CH:15]/[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([OH:31])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C/C(=C\COc1ccc(C(C)C(=O)O)cc1)c1ccc2c(c1)Cc1ccccc1-2
Yield: 73.6 %

Procedure:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester (example 18) (220 mg, 0.53 mmol) was suspended in 1N NaOH (5.5 ml) and methanol (20 ml) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (50 ml) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (50 ml) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The residue was recrystallised from boiling ethanol (20 ml) to give 150 mg (73%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O>[C:43]1([NH:42][C:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 66 h
Yield: 71.2 %

Procedure:
To a suspension of 4-bromo-pyridine-2-carboxylic acid (1.00 g, 5.00 mmol) in dimethylformamide (10 mL) was added 1-methylmorpholine (1.1 mL, 10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HATU) (2.37 g, 6.23 mmol). The mixture became an orange solution after 10 minutes. Aniline (0.5 mL, 5.5 mmol) was added and the solution was stirred at room temperature for 66 hours. The dimethylformamide was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The separated water layer was extracted with ethyl acetate. The combined ethyl acetate extract was washed with water and saturated sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to crude 2. Chromatography on silica gel (40 g) applied in dichloromethane and eluted with hexanes:ethyl acetate (1:1) gave the title compound (0.986 g, 71%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:2]([NH:50][C:45]3[C:44]4[CH:43]=[N:42][N:41]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[C:49]=4[CH:48]=[CH:47][CH:46]=3)=[N:3][CH:4]=2)=[CH:28][CH:29]=1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Reactant: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COCc2cnc(Nc3cccc4c3cnn4C3CCCCO3)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 77.2 %

Procedure:
6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.223 g, 2.634 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.596 g, 2.74 mmol) were dissolved in THF (23.5 mL) and the flask was cooled in an ice water bath under nitrogen. Then, LiHMDS (1.0 M in THF, 7.8 mL, 7.8 mmol) was added via syringe, and the reaction was stirred under nitrogen at 0° C. for 35 minutes. Then, the reaction was quenched with water (40 mL) and diluted with water (40 mL), and then extracted with DCM and with 10:1 DCM/MeOH. Brine was added to break up emulsions. The organic extracts were combined, concentrated, and purified on a silica gel filter (about 3 inches, 50:1 DCM/2 N ammonia in MeOH to 40:1 DCM/2 N ammonia in MeOH) to afford N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.343 g, 54% purity, 43% yield). MS (ESI pos. ion) m/z 661 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:4]([C:24]([F:25])([F:27])[F:26])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C=O)c2-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CO)c2-c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
To a solution of the aldehyde prepared in Step 2 (165 mg, 0.41 mmol) in methanol (3.5 mL) at 0° C. was added sodium borohydride (16 mg, 0.41 mmol). The reaction solution was kept at 0° C. for 2.5 hours. The reaction was quenched with the addition of an aqueous 1M KHSO4 solution (3 mL). The mixture was extracted with dichloromethane and the organic solution dried and concentrated. The residue was chromatographed on silica (1:1 hexane:ethyl acetate) to give the desired product (36 mg, 46%): m.p. 179°-180° C.; 1H NMR d 7.91 (m, 2H), 7.53-7.40 (m, 5H), 6.75 (s, 2H), 4.53 (d, 2h, J=5.0 Hz), 4.30 (t, 1H, J=5.0 Hz).