Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=S)[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].ClCC(O)=[O:17]>>[CH2:1]([C:5]1[C:6](=[O:13])[NH:7][C:8](=[O:17])[NH:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCl
Reactant: CCCCc1c(C)[nH]c(=S)[nH]c1=O
Product: CCCCc1c(C)[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 5-butyl-6-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one in 10% aqueous chloroacetic acid (100 mL) is stirred at reflux for 3 hours and then allowed to cool to room temperature. The suspension is cooled in an ice bath for a few minutes and then filtered. The solid is thoroughly washed with H2O and dried, yielding pure 5-butyl-6-methyl-1H-pyrimidine-2,4-dione as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 10.86 (br s, 1H), 10.57 (br s, 1H), 2.17 (m, 2H), 2.01 (s, 3H), 1.25 (m, 4H), 0.85 (t, J=6.9 Hz, 3H) ppm. MS: m/z 183 [M+1].
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([F:26])([F:25])[C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:5][CH2:6][C:7]([F:25])([F:26])[C:8]([F:23])([F:24])[C:9]([F:21])([F:22])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(C(=O)O)cc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)cc1

Procedure:
4-Octyloxyphenyl 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoate (Compound 4, Table 1) was prepared by esterification of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoic acid (prepared essentially as in Example 9) with 4-octyloxyphenol .
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[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.[OH-].[K+]>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (20 g, 0.05 mol) in MeOH (200 mL), a solution of KOH (12.6 g, 0.22 mol) in water (50 mL) was added dropwise and the reaction mixture was stirred for 1 h at RT. The methanol was then removed and the reaction mixture was washed with EtOAc (2×100 mL) and acidified to pH˜3 with 1 N HCl at 0° C. The precipitated solid was then filtered and dried to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (15 g, 92%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.[CH3:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(S)cc1C
Reactant: O=C1Nc2ccc(OCCCCCl)cc2CO1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>O.CS(C)=O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.2 g (0.2 mole) of potassium hydroxide in 15 ml of water are added dropwise under nitrogen atmosphere to 22 g (0.2 mole) of 4-aminophenol in 100 ml of diemthylsulfoxide. 36 g (0.2 mole) of 2-chloro-5-(trifluoromethyl)pyridine in 30 ml of dimethylsulfoxide are added dropwise at 25° C. The reaction mixture is stirred for 3 hours at room temperature, then poured into ice-water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in ether and the ether solution is extracted with 1 N hydrochloric acid. The acid phase is made alkaline with concentrated NaOH solution and extracted with ether. The ether phase is dried over sodium sulfate and concentrated by evaporation, affording 4-(5-trifluoromethylpyridin-2-yl-oxy)aniline as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16]C(=O)[C@@H:14]2[C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:20]=2)=[CH:8][CH:9]=1)=[O:4].CCN(CC)CC.[CH:48]([Cl:51])(Cl)[Cl:49]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:48]([Cl:51])([Cl:49])[C@@H:14]2[C:19]2[CH:20]=[CH:21][C:22]([CH:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@H]2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Cl)Cl)cc1
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of Hydrazone 2 (prepared from 0.11 mmol of ketone as described above) in 1 mL CHCl3 was cannula transferred to a mixture of CuCl2 (107 mg, 0.80 mmol) and Et3N (50 μL, 0.36 mmol) in MeOH (1.2 mL), rinsing with 1 mL CHCl3. After 1 h, a solution of 10% conc. NH4OH/saturated NH4Cl (8 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined CH2Cl2 solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0%→20% ethyl acetate/hexanes) gave compound 4 (34 mg, 49%).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:40].O>C(O)C>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[C:17](=[O:24])[CH:18]=[C:19]([C:21]([O-:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[Na+:40]
Reactant: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)[O-])oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
To 5.0 parts of 7-[3-(4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid dissolved in 200 parts of hot ethanol was added a solution of 0.870 parts of sodium bicarbonate in 30 parts of water. The solution was evaporated under reduced pressure to dryness, dry benzene was added and the mixture was again evaporated to dryness. The resulting buff solid was ground to a powder and dried to afford 5.0 parts of sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[S:10][C:9]=2[C:24](OCC)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[NH:7]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[S:10][C:9]=1[C:24]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])=[O:25])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Product: CC(C)(CO)NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Yield: 16 %

Procedure:
A mixture of Example 1 and 2-amino-2-methyl-1-propanol (1.22 mL, 13 mmol) was heated at 150° C. for 16 h. The mixture was partitioned between DCM (60 mL) and 10% citric acid (75 mL). The aqueous phase was extracted with DCM (20 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, 40% EtOAc in DCM) gave the title compound as a pale brown solid (45 mg, 16%). δH (CDCl3) 8.44 (1H, br s), 7.56-7.46 (3H, m), 7.34-7.31 (2H, m), 7.26-7.20 (3H, m), 7.03-6.96 (3H, m), 6.33 (1H, d, J 9.7 Hz), 5.65 (1H, br s), 4.21-4.18 (1H, br m), 3.49 (2H, d, J 5.5 Hz), 1.18 (6H, s). LCMS (ES+) 434 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:29]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 150 mg, 0.78 mmol) was dissolved in CH2Cl2 (5 mL) and to the resultant solution were added DIPEA (221 mg, 1.71 mmol) and 3,5-dichlorobenzoyl chloride (178 mg, 0.85 mmol) in the given order. The mixture was stirred for 4 h at room temperature, diluted with CH2Cl2 (20 mL), and then washed with water (10 mL), aqueous KHSO4 (1M, 10 mL) and brine (10 mL). The organic solution was dried over Na2SO4. The solvent was removed by evaporation and there was obtained 214 mg (75%) of 3,5-dichloro-N-[(2S)-2-(4fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide as an oil. 1H NMR (500 MHz, CDCl3): 2.2-2.4 (cm, 2H), 2.6 (s, 2H), 2.9-3.9 (cm, 4H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.7 (s, 1H), 6.9-7.4 (cm, 6H); LCMS: m/z 367 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([C:13](=[O:16])[NH:14][CH3:15])[C:6]=2[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.Cl.[CH3:53][NH:54][O:55][CH3:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([N:54]([O:55][CH3:56])[CH3:53])=[O:12])=[C:7]([C:13]([NH:14][CH3:15])=[O:16])[C:6]=2[CH:17]=1
Reactant: CNOC
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C(=O)N(C)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (1 g, 2.47 mmol), HOBT (500 mg, 3.70 mmol) and EDCI (946 mg, 4.94 mmol) in DMF (20 mL) was stirred at room temperature under N2 for 2 h. Et3N (1.25 g, 12.34 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.03 g, 12.34 mmol) were added, then the mixture was stirred for 18 h. The mixture was concentrated, diluted with water, extracted with EA, the organic layers were washed with Na2CO3 (a.q.), brine, dried over Na2SO4, concentrated. The residue was purified by column chromatography (DCM:EA=20:1) to get product 5-bromo-N2-methoxy-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (0.68 g, yield: 62%). 1H-NMR (CDCl3, 400 MHz) δ 8.83 (s, 1H), 8.74 (s, 1H), 7.72 (s, 1H), 3.89 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H), 3.08 (s, 3H), 2.98 (d, J=4.8 Hz, 3H). MS (M+H)+: 448/450.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([F:36])[C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:30]3([C:29]([F:37])([F:36])[F:28])[CH2:32][CH2:31]3)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=415.4 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][C@H:48]4[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][O:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][C@H:48]4[CH2:53][CH2:52][CH2:51][N:50]([C:67](=[O:68])[CH2:66][O:65][CH3:64])[CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCC[C@H](Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.9 %

Procedure:
HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.202 g); 1H NMR Spectrum: (DMSO d6 373K) 1.60 (m, 1H), 1.88 (m, 2H), 2.10 (m, 1H), 3.32 (s, 3H), 3.51 (m, 2H), 3.62 (m, 1H), 3.87 (m, 1H), 3.98 (s, 3H), 4.02 (d, J=14 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 4.66 (m, 1H), 7.26 (m, 1H), 7.33 (s, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 7.83 (s, 1H), 8.40 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([N:14]([CH3:18])[CH2:15][C:16]#[CH:17])[CH2:8]OS(C)(=O)=O.[F-:19]>>[F:19][CH2:8][CH:7]([N:14]([CH3:18])[CH2:15][C:16]#[CH:17])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN(C)C(COS(C)(=O)=O)Cc1ccco1
Reactant: [F-]
Product: C#CCN(C)C(CF)Cc1ccco1

Procedure:
Compound 3e is synthesized by general procedure A from starting material 3c with F-18 fluoride 0.96 GBq. The desired compound is obtained (124 MBq).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[OH:32][C:30]([C:29]([F:34])([F:33])[F:28])=[O:31].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2cc(OC3CCNCC3)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate (1.50 g, 3.84 mmol) in dichloromethane (10 mL) and added 2,2,2-trifluoroacetic acid (0.888 mL, 11.5 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to provide 4-methyl-N-(4-(piperidin-4-yloxy)pyridin-2-yl)thiazol-2-amine TFA salt (1.6 g, 100%) as a light yellow solid. 1H NMR (DMSO) δ 8.53 (bs, 2H), 8.15 (d, 1H), 6.67 (dd, 1H), 6.61 (m, 1H), 6.56 (d, 1H), 4.74 (m, 1H), 3.25 (bm, 2H), 3.11 (bm, 2H), 2.23 (d, 3H), 2.10 (bm, 2H), 1.84 (bm, 2H); Mass spectrum (apci) m/z=291 (100) (M+H).
Reaction SMILES: [CH2:1]([O:19][C@@H:20]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:21]1[N:28]1[C:38]2[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=2[N:30]=[CH:29]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[Si](Cl)(C)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46]>N1C=CC=CC=1>[C:44]([NH:36][C:35]1[NH:34][C:32](=[O:33])[C:31]2[N:30]=[CH:29][N:28]([C:38]=2[N:37]=1)[C@@H:21]1[O:22][C@H:23]([CH2:26][OH:27])[C@@H:24]([OH:25])[C@H:20]1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Yield: 55.9 %

Procedure:
2'-O-Octadecylguanosine (1.9 g) in pyridine (150 ml) was treated with trimethylsilyl chloride (2 g, 5 eq) and isobutyryl chloride (2 g, 5 eq) as per the procedure of Example 4. The product was purified by silica gel chromatography (eluted with 3% MeOH/EtOAc) to yield 1.2 g of product. 1H NMR (DMSO-d6) δ 0.85 [t, 3, CH3 ], 1.15 [m, 38, O--CH2CH2 (CH2)16, CH(CH3)2 ], 2.77 [m, 1, CH(CH3)2 ], 4.25 (m, 2, 2'H, 3'H); 5.08 (t, 1, 5'-OH), 5.12 (d, 1, 3'-OH), 5.87 (d, 1, 1'-H), 8.27 (s, 1, 8-H), 11.68 (s, 1, NH2) and 12.08 (s, 1, NH2). Anal. Calcd. for C32H55N5O6 : C, 63.47; H, 9.09; N, 11.57. Found: C, 63.53; H, 9.20; N, 11.52.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:23][CH2:22][C:9]2([O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][C:9]3([CH2:22][CH2:23][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[O:13][N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(c1cccc(OC)c1)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C2=NOC3(CCC(C(=O)O)CC3)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-methoxyphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (51 g, 161 mmol) in MeOH (1000 ml) and lithium hydroxide monohydrate (18 g, 241 mmol) in H2O (145 ml) was stirred overnight at RT.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:39]=[CH:38][CH:37]=[CH:36][C:10]=1[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]#[CH:25])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[N:14][C:13]1=[O:35].[CH3:40][NH:41][CH3:42]>>[CH3:40][N:41]([CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:39]=[CH:38][CH:37]=[CH:36][C:10]=1[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24]#[CH:25])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[N:14][C:13]1=[O:35]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCCCCCCl
Reactant: CNC
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCCCCCN(C)C
Temperature: 60 °C

Procedure:
A mixture of 50 mg (92.1 μmol) 1-[2-(6-chloro-hexyloxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one and 160 μl ethanolic dimethylamine solution (33%) is heated at 60° C. for 18 h. Extraction with dichloromethane and aqueous 0.1 M NaOH yields the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:31]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)nc4)cnc3s2)cc1OC
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)nc4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(2-piperazin-1-yl-pyrimidin-5-yl)-imidazo[2,1-b][1,3,4]thiadiazole (52 mg, 0.113 mmol, 1 eq), Et3N (0.032 mL, 0.226 mmol, 2 eq), formaldehyde (0.102 mL, 1.36 mmol, 12 eq) and acetic acid (0.02 mL, 0.136 mmol, 1.2 eq) in MeOH (2 mL) was added Sodium cyanoborohydride (0.1 g, 1.58 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified by HPLC to give the desired product (6 mg, 12%). HPLC-MS: (5-40% B in 8 min, 0.8 mL/min, 50° C.): tR=4.64 min, [M+H]+ m/z 438.2; 1H NMR (300 MHz, DMSO) δ 8.98 (s, 2H), 7.70 (s, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 2.38 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.08 h
Yield: 24.9 %

Procedure:
3-Methyl-2-pyridinecarboxylic acid (11 mg, 0.08 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken then left to stand at room temperature overnight. Solvent was removed in vacuo and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (5.5 mg) as a pale yellow gum.