Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOCCn1ccnc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 68.0 g of imidazole, 318 g of 2-[2-(2-methoxyethoxy)ethoxy]ethyl p-toluenesulfonate, 276 g of potassium carbonate, and 1,000 g of N,N-dimethylformamide was heated and stirred at 100° C. for 16 hours. To the reaction solution was added ethyl acetate. The precipitate was filtered off, after which the solvent was distilled off in vacuo. The residue was purified by distillation in vacuo, obtaining 163 g of 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-1H-imidazole (boiling point 121° C./16 Pa, yield 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]1[N:10]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:11](=[O:35])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][C:15]([O:27]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]1[N:10]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:11](=[O:35])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])=[CH:16][C:15]([OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(OCCCC(F)(F)F)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.09 g, 5.5 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.48 g, 95.4%) as crystals.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C.[OH-].[Na+]>C1COCC1.O>[CH2:6]([C:13]1[CH:18]=[C:17]([B:22]([OH:25])[OH:23])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cc1Cc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
8.61 ml (13.8 mmol, 1 eqv) of a 1.6 M solution of n-BuLi in hexanes was added to a solution of 3.82 g (13.8 mmol) 2-Benzyl-4-bromo-anisol (21) in 100 ml dry THF at −78° C. After stirring this mixture for 30 min at −78° C., 4.70 ml (41.4 mmol, 3 eqv) B(OMe)3 was added and the solution was stirred for 24 h at rt. Now 10 ml water and 25 ml of a 10% aq. NaOH-solution were added and stirring was continued for further 60 min. Then the pH was adjusted to 4-5 with 1-N-HCl-solution and most of the solvent was evaporated. The residue was extracted with EtOAc and the comb. org. fractions were dried over MgSO4 and evaporated, which led after drying in high vacuum to 3.33 g (13.8 mmol, 100%) of an orange solid. This crude boronic acid 22 was used without further purification: 1H NMR (500 MHz, CDCl3) δ 3.81 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H, J=8.20 Hz), 7.10-7.23 (m, 5H), 7.79 (d, 1H, J=1.58 Hz), 7.96 (dd, 1H, J1=8.20 Hz, J2=1.73 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[NH:5][C:6]=1[CH2:7][OH:8].C([O-])([O-])=O.[K+].[K+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:5]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[C:6]=1[CH2:7][OH:8]
Reactant: CCCCCCCc1nc(Cl)c(CO)[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 118.8 %

Procedure:
To a solution of 4-chloro-2-heptyl-5-(hydroxymethyl)imidazole (5.2 g, 20.7 mmol) in dry DMF (100 mL) was added anhydrous K2CO3 (4.3 g, 31.1 mmol) followed by 4-nitrobenzylbromide (5.4 g, 24.9 mmol). The solution was stirred 3-5 hours at 65°-70°. The reaction mixture was poured into a separatory funnel containing EtOAc and H2O (300 mL each). The aqueous phase was extracted with EtOAc (150 mL) and the combined organic phases were washed three times with H2O (150 mL) before being dried (MgSO4), filtered and concentrated to give 9.0 g brown crude oil. Chromatography (silica gel, 450 g; 1:1 EtOAc/hexanes) gave 1.3 g (17% overall, 35% of theoretical); m.p. 110°-115°. NMR (200 MHz, CDCl3) δ8.20 (d, 2H, 5 Hz); 7.20 (d, 2H, 5 Hz); 5.35 (s, 2H); 4.45 (s, 2H); 3.10-3.00 (m, 1H); 2.50 (t, 2H, 5 Hz); 1.75-1.50 (m, 2H); 1.40-1.10 (m, 8H); 0.90-0.75 (m, 3H). Mass Spec. 365.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])=[C:12]([C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]([CH3:25])[CH:15]=2)[CH:13]=1>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[O:26][C:11]1[CH:10]=[CH:9][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[C:14]1[C:23]2[C:18](=[CH:19][N:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]([CH3:25])[CH:15]=1
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2ccncc2c1=O
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3cnccc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to 4-[5-amino-2-(2,4-difluorophenoxy)phenyl]-2-methyl-2,7-naphthyridin-1-one (25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at room temperature for 18 h and then purified by preparative HPLC to give the title compound (8.5 mg, 27.4%) as yellow gum. 1H NMR (Methanol-d4, 400 MHz) δ 9.54 (s, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.00 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.09-6.99 (m, 2H), 6.96-6.94 (d, J=8.4 Hz, 1H), 6.91-6.85 (m, 1H), 3.70 (s, 3H), 3.15 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). LCMS: 472.1 (M+H)+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:10]1.C(N(CC)CC)C.[CH:44]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45]1>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:26][S:47]([CH:44]4[CH2:46][CH2:45]4)(=[O:49])=[O:48])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:27]([C:33]([F:36])([F:34])[F:35])([C:29]([F:31])([F:30])[F:32])[OH:28])=[N:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
1-(2-Chloro-phenyl)-5-{4-[4-amino-piperidin-1-yl]-phenyl}-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 331, triethylamine (37.3 uL, 0.27 mmol) and cyclopropanesulfonyl chloride (10.4 mg, 0.08 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:21]([C:25]1[N:26]=[N:27][C:28](Cl)=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH3:24].O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[N:27]=[N:26][C:25]([CH2:21][CH2:22][CH2:23][CH3:24])=[C:30]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:35][CH:36]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (94.2 mmol, 18.97 g) in THF (100 mL) at room temperature was added potassium tert-butoxide (87.0 mmol, 9.76 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (72.5 mmol, 25.0 g) in THF (100 mL). The reaction mixture was allowed to slowly attain room temperature while stirring overnight. The reaction was poured into a mixture of water (300 mL) and ethyl acetate (300 mL). The mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 330 g SiO2 cartridge using an ethyl acetate/hexanes gradient to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [I-].C[N+:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(C)(C)[C:4]=1C>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:11]1([NH:3][CH:4]=[N:3][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC1=[N+](C)c2ccccc2C1(C)C
Agent: [I-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C(=Nc1ccccc1)Nc1ccccc1
Yield: 8 %

Procedure:
Unfortunately, the hemicyanine intermediates are notoriously difficult to obtain in good yields and/or in a pure form. For example, the condensation of N-methyl-2,3,3-trimethyl[3H]indolium iodide with malonaldehyde dianil monochloride in acetic anhydride is said (Piggott and Rodd, BP 355,693/1930) to give rise to a green intermediate, indicating a strong contamination of the desired, yellow hemicyanine intermediate (yellow) with symmetric, blue indocyanine dye, FIG. 2. Moreover, when F. M. Hamer, in “Some Unsymmetrical Pentamethincyanine Dyes and their Tetramethin Intermediates” tried to prepare a pure sample of the same hemicyanine intermediate, obtained it in an 8% yield, after a lengthy and wasteful procedure based on multiple extractions and precipitations. More recently, R. B. Mujumdar, L. A. Ernst, Swati R. Mujumdar, C. J. Lewis, and A. S. Waggoner, in “Cyanine Dye Labelling Reagents: Sulfoindocyanine Succinimidyl Esters”, Bioconjugate Chemistry, 4, 105, (1993) described the synthesis of hemicyanine intermediates for the preparation of sulfoindocyanine dyes active esters, useful as labelling reagents. One intermediate was obtained by condensing 1-ethyl-2,3,3-trimethyl[3H]indolium-5-sulfonate with N,N′-diphenylformamidine in acetic acid for four hours. While the reported yield of the crude compound was 30%, the carboindocyanine dyes prepared from it were obtained only in 25% and 5% yields, after extensive purification by reverse phase HPLC chromatography. Similarly, the condensation of 1-ethyl-2,3,3-trimethyl[3H]indolium-5-sulfonate with malonaldehyde dianil hydrochloride in a mixture of acetic acid and acetic anhydride at reflux for four hours was said to produce the corresponding hemicyanine intermediate in an unreported yield. Again, the yields of the dicarboindocyanine dyes obtained from these intermediates were very low (5%). In fact, when Mank (Anal. Chem., 67, 1744) tried to synthesise the same dicarbocyanine label described in the previous reference he obtained a total yield of 18% of dicarbocyanines, from which the desired product was difficult to separate. He then devised an alternative approach based on 1,3,3-trimethoxypropene. Unfortunately, this chemical is no longer available commercially. Similar difficulties were encountered by us when trying to repeat the syntheses indicated above.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[CH3:31])[NH:27][N:26]=[CH:25]2>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][C:30]=3[CH3:31])[NH:27][N:26]=[CH:25]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc2[nH]ncc2cc1N
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: Cc1cc2[nH]ncc2cc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 5-amino-6-methylindazole (Bionet), the title compound was obtained as an off-white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)cc(F)c1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccccc2)cc(F)c1C#N
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25][CH2:26][CH2:27][CH2:28]O)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C1(C)C(S([Cl:39])(=O)=O)=CC=CC=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:39][CH2:28][CH2:27][CH2:26][S:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([C:8]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:11][N:10]4[CH2:12][CH2:13][CH2:14][C:9]=34)=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: OCCCSc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: ClCCCSc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Preparation #21, 3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ylsulfanyl]-propan-1-ol (25.0 mg, 0.062 mmol) in dry pyridine (0.1 mL) is added toluene sulfonyl chloride (60.0 mg, 0.31 mmol) and the resulting mixture stirred at room temperature for 72 h. Saturated sodium bicarbonate solution is added and the resulting solution extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification of the residue on SiO2 (5% to 10% methanol in dichloromethane) gives the desired product, 11.2 mg (43%). MS ES+ m/e 421.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:44]4[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: O=S1(=O)CCNCC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCS(=O)(=O)CC3)sc2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and thiomorpholine 1,1-dioxide (109 mg, 807 μmol), and the mixture was stirred at 60° C. for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (94 mg, 56%) as a colorless solid.
Reaction SMILES: F[B-](F)(F)F.[FH:6].F.F.C(N(CC)CC)C.C(N(CC)CC)C.[CH:23]1(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:6][CH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: OC1CCCCCCC1
Reactant: F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: C1=CCCCCCC1
Product: FC1CCCCCCC1
Reaction time: 24 h

Procedure:
Procedure for the fluorination of alcohols in various solvents (examples 62-67): To a mixture of the diethylaminodifluorosulfinium tetrafluoroborate (344 mg, 1.5 mmol), triethylamine trihydrofluoride (326 μL, 2.0 mmol) and triethylamine (139 μL, 1.0 mmol) in the solvent (3.0 mL), at room temperature and under nitrogen, is added cyclooctanol (132 μl, 1.0 mmol). The reaction mixture is stirred for 24 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using pentane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide fluorocyclooctane of admixed with cyclooctene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:20]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccccc3F)C2)c1

Procedure:
The compound of Example 1 was prepared according to the general preparation protocol A from 2-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])([O-:24])=[O:23]>O1CCCC1.CCCCCC>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]([C:15]1[C:14]([Br:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=1)[OH:28])([O-:24])=[O:23]
Reactant: COc1ccc(Br)cn1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Reaction time: 3 h
Yield: 130.8 %

Procedure:
n-Butyllithium (17.5 ml of a 1.6M hexane solution)in anhydrous tetrahydrofuran (20 ml) was added dropwise to a stirred, cooled (-72° C.) solution of diisopropylamine (3.8 ml) in anhydrous tetrahydrofuran (120 ml) under a nitrogen atmosphere. 5-Bromo-2-methoxypyridine (5.09 g, Eur. J. Med. Chem. 1977, 12, 531) in anhydrous tetrahydrofuran (15 ml) was added dropwise followed by a solution of 2-nitrobenzaldehyde (2.96 g) in anhydrous tetrahydrofuran (20 ml) keeping the temperature of the reaction mixture below -70° C. The reaction mixture was stirred for 3 hours at -60° C. to -70° C. then quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with water then dried (magnesium sulphate) and evaporated to dryness. The residue was combined with crude product from another reaction of identical scale then purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:4) and the solid obtained recrystallised from dichloromethane/petroleum ether (60-80) to afford the title compound (8.69 g). mp 128°-131° C. Rf =0.69 in 20% diethyl ether/dichloromethane on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.93 (3H, s), 6.42 (1H, s), 7.00 (1H, s), 7.31 (1H, dd, J=1 and 7 Hz), 7.49 (1H, ddd, J=1 and 7 Hz), 7.58 (1H, ddd, J=1 and 7 Hz), 8.02 (1H, dd, J=1 and 7 Hz), 8.19 (1H, s); IR (KBr) 3600-2800 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C(Cl)Cl>[CH:31]1([C:34]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:8]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of Compound 17c (0.5 g; 1.6 mmol) in CH2Cl2 (6 mL) was added Et3N (0.72 mL; 6.4 mmol) and cyclopropylcarbonyl chloride (0.19 mL; 2.1 mmol). The solution was stirred at room temperature for 1 h, then poured the reaction mixture into water. Filtered to collect the solid and dried to afford Compound 17d (410 mg; 68% yield). MS: m/z 376.1 (M+H)+.