Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[C:6]([O:16][CH2:17][O:18][CH3:19])[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[CH3:34].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.[Cu]I>[CH3:14][C:11]1([CH3:15])[CH2:12][O:13][CH:8]([C:7]2[C:6]([O:16][CH2:17][O:18][CH3:19])=[C:5]([O:20][CH3:21])[CH:4]=[CH:3][C:2]=2[NH:22][CH2:23][C@@H:24]([OH:35])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=2[CH3:34])[O:9][CH2:10]1
Reactant: Cc1ccc(OC[C@H](O)CN)c(C)c1
Reactant: COCOc1c(OC)ccc(Br)c1C1OCC(C)(C)CO1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COCOc1c(OC)ccc(NC[C@@H](O)COc2ccc(C)cc2C)c1C1OCC(C)(C)CO1
Temperature: 90 °C
Yield: 641.3 %

Procedure:
A mixture of 2-(6-bromo-3-methoxy-2-methoxymethoxy-phenyl)-5,5-dimethyl-[1,3]dioxane (36 mg, 0.1 mmol), (R)-1-amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (30 mg, 0.15 mmol), CuI (51.4 mg, 0.27 mmol), ethylene glycol (168 mg, 2.7 mmol), and K3PO4 (573 mg, 2.7 mmol) in 2-propanol (8 mL) was heated at 90° C. in a sealed vial for 14 h and evaporated. Chromatography of the residue with hexanes and EtOAc afforded the title compound (305 mg, 71%). 1H NMR (CDCl3) δ 0.79 (s, 3H, CH3), 1.29 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.95 (br s, 1H, OH), 3.30 (m, 1H), 3.49 (s, 3H, OCH3), 3.51 (m, 1H), 3.65 (m, 2H), 3.75 (s, 3H, OCH3), 3.77 (m, 2H), 4.00 (m, 2H), 4.25 (m, 1H), 5.09 (s, 2H), 6.05 (s, 1H), 6.48 (d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, H), 6.82 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 6.95 (s, 1H). ESI-MS m/z 476.8 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:37](O)(=[O:46])/[CH:38]=[CH:39]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[C:37](=[O:46])/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(CCN(Cc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3′-[{2-[4-(Aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide (506 mg), trans-cinnamic acid (163 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 211 mg) and 1-hydroxybenzotriazole (HOBT; 149 mg) were dissolved in a mixed solvent of dichloromethane (15 ml) and DMF (7 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and water was added to the residues which were then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (dichloromethane/methanol=98/2), whereby the title compound (284 mg) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15].C(N(CC)CC)C>C1COCC1>[CH3:15][C:14]([OH:16])([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(O)CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)CCNc1ccccc1[N+](=O)[O-]
Yield: 83.2 %

Procedure:
A solution of 1-fluoro-2-nitrobenzene (1.9 mL, 18 mmol), 4-amino-2-methyl-2-butanol (1.6 g, 15 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (30 mL) was refluxed for 8 h. Then the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1) to afford 2.8 g (82%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C1COCC1.CO>[Cl:20][C:17]1[N:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.9 %

Procedure:
[1-(6-Chloro-pyridazin-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.59 g 1.89 mmol) was dissolved in THF:MeOH 2:1 (45 ml) and HCl in 1,4-dioxan (4M, 3.8 ml, 7.56 mmol) was added. The reaction was stirred at rt for 3 h and then at 60° C. for 2 h. The solvent was evaporated to yield the title compound (0.49 g, 100%) as the hydrochloric salt. 1H-NMR (CD3OD, 500 MHz): δ 8.10 (d, 1H), 7.92 (d, 1H), 4.41-4.35 (m 2H), 3.67-3.57 (m, 1H), 3.55-3.46 (m, 2H), 2.32-2.24 (m, 2H), 1.96-1.83 (m, 2H).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:21]([OH:24])([CH3:23])[CH3:22])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)(C)C.O>[Cl:20][C:16]1[N:17]=[C:18]([Cl:19])[C:13]2[CH:12]=[C:11]([C:21]([OH:24])([CH3:22])[CH3:23])[NH:10][C:14]=2[N:15]=1
Reactant: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Lithium diisopropylamide (2 mL, 4.0 mmol, 2 M in THF) was added dropwise to a solution of 7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (656 mg, 2.0 mmol) in anhydrous THF (15 mL) at −78° C. The resulting solution was stirred at −78° C. for 90 min, then acetone (0.4 mL, 5.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo affording 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol. To a solution of 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (2 mmol) in a mixture of isopropyl alcohol (11 mL) and water (3 mL) was added sodium hydroxide (6 mL, 36 mmol, 6M aqueous solution). The resulting mixture was stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 2-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 64%). LCMS (method A): RT=2.70 min, [M]−=244/246.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH:13]([Cl:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:35][CH:13]([Cl:12])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Reaction time: 20 h
Yield: 76.4 %

Procedure:
1.2 ml (0.0129 mol) of acetic anhydride and 0.6 ml (0.0143 mol) of 98% strength nitric acid are added in succession to 5 g (0.0113 mol) of 5-dichloroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 10 ml of glacial acetic acid at room temperature. The mixture is stirred for 20 hours, after which it is evaporated down in vacuo, the residue is taken up in 50 ml of dichloromethane and the solution is washed in succession with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent in vacuo. 4.2 g (76.4% of theory) of 5-dichloroacetamido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 112° C.-120° C. are obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (S)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to −20° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 91% (2R,3S)/(2S,3S)=92/8). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.10 (s, 6H), 0.92 (s, 12H), 3.85 (d, 1H, J=12.0 Hz), 4.07 (d, 1H, J=12.0 Hz), 4.35 (q, 1H, J=6.6 Hz), 6.77-6.79 (m, 1H), 6.93-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:22]=2[Cl:29])[C:16]([NH2:20])=[N:17][C:18]=1[NH2:19])#N.C[OH:31]>C1(C)C=CC=CC=1>[CH:11]([C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:22]=2[Cl:29])[C:16]([NH2:20])=[N:17][C:18]=1[NH2:19])=[O:31]
Reactant: CO
Reactant: N#Cc1nc(-c2cc(Cl)cc(Cl)c2Cl)c(N)nc1N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminium hydride (1.5 M in toluene) (2.12 ml, 3.18×10−3 mole) was added dropwise at 0° C. under nitrogen to a suspension of 5-Cyano-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.5 g, 1.59×10−3 mole) in dry toluene (70 ml) and the reaction was stirred at 0° C. for 1 hr. A further one equivalent of diisobutylaluminium hydride was then added and the mixture again stirred at 0° C. for 1 hr. Methanol (1 ml) was added carefully at 0° C. under nitrogen to destroy excess hydride and the reaction was warmed to room temperature. Ethyl acetate (100 ml) was added and the solution was washed with 5% citric acid solution (2×100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the desired product. Yield 0.340 g (67%), N.m.r. (D6DMSO) δ: 7.53 (1H, d), 7.91 (1H, d), 6.90-7.80 (4H, b), 9.49 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C@@H:17]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:16]([CH3:38])[O:15][C:14]2=[O:39])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[CH2:48]([O:50][CH2:51][C:52]([O:54][CH2:55]Cl)=[O:53])[CH3:49]>CC(C)=O>[CH2:48]([O:50][CH2:51][C:52]([O:54][CH2:55][O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C@@H:17]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:16]([CH3:38])[O:15][C:14]2=[O:39])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:53])[CH3:49]
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](Cc3ccc(C)cc3)[C@@H](OCCCC(F)(F)F)[C@H](C)OC2=O)c1O
Reactant: CCOCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOCC(=O)OCOc1c(OC)ccnc1C(=O)N[C@H]1CCC[C@H](Cc2ccc(C)cc2)[C@@H](OCCCC(F)(F)F)[C@H](C)OC1=O
Temperature: 40 °C
Reaction time: 17 h
Yield: 55.3 %

Procedure:
To a 25 mL screw top vial were added 3-hydroxy-4-methoxy-N-((3S,7R,8R,9S)-9-methyl-7-(4-methylbenzyl)-2-oxo-8-(4,4,4-trifluorobutoxyl)oxonan-3-yl)picolinamide (87.9 mg, 0.159 mmol), Na2CO3 (33.8 mg, 0.319 mmol), NaI (6.3 mg, 0.264 mmol), anhydrous acetone (2 mL), and chloromethyl 2-ethoxyacetate (40.8 mg, 1.68 mmol), and the resulting mixture was warmed to 40° C. and stirred for 17 h. The reaction was cooled to room temperature, concentrated under a stream of nitrogen, and purified by column chromatography on SiO2 (2→40% acetone/hexanes) to provide the title compound as a colorless oil (58.8 mg, 52%): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=8.1 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.93 (d, J=5.4 Hz, 1H), 5.80 (s, 2H), 4.89 (dq, J=9.1, 6.4 Hz, 1H), 4.55 (dt, J=10.9, 7.4 Hz, 1H), 4.08 (s, 2H), 3.88 (s, 3H), 3.80 (dt, J=8.9, 6.1 Hz, 1H), 3.64-3.54 (m, 3H), 3.17 (t, J=9.0 Hz, 1H), 2.96 (dd, J=13.3, 3.4 Hz, 1H), 2.40-2.13 (m, 7H), 1.92-1.76 (m, 3H), 1.65-1.37 (m, 6H), 1.30-1.14 (m, 4H), 0.93-0.80 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.62, 169.97, 162.83, 160.09, 145.73, 143.81, 142.18, 137.20, 135.41, 129.02, 128.58, 131.42-122.86 (m), 109.65, 89.44, 84.20, 74.83, 71.60, 67.71, 67.10, 56.15, 51.69, 45.80, 36.42, 33.56, 30.73 (q, J=29.0 Hz), 26.62, 23.01 (q, J=3.1 Hz), 20.93, 18.75, 18.05, 14.94; 19F NMR (376 MHz, CDCl3) δ −66.35, ESIMS: m/z 669 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]([O:8][CH:9]2[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10]2)=[N:6][CH:7]=1.CN([CH:25]=[O:26])C.[CH2:27]([N:29](CC)CC)C>O.CCOC(C)=O>[CH3:25][O:26][N:29]([CH3:27])[C:13]([CH:11]1[CH2:10][CH:9]([O:8][C:5]2[C:4]([CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[CH2:12]1)=[O:14]
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Solvent: O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1

Procedure:
To a solution of 3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutanecarboxylic acid (1.5 g, 4.68 mmol) was added DMF (20 mL), triethylamine (1 mL, 7.02 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (2.24 g, 5.90 mmol). The reaction mixture was stirred at RT for 1d. Then it was diluted with water and EtOAc. The organic layer was separated and the aqueous phase was extracted with EtOAc (2×10 mL). All the organic layers were combined and washed with brine (1×10 mL), dried over MgSO4, filtered, and concentrated to get a crude, which was purified by flash column chromatography on silica gel (30% to 70% EtOAc in hexanes) to give the product (2.2 g) as yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C=CC=CC=1>ClCCl>[C:1]([N:14]1[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of 73.1 g (520 mmol) of benzoyl chloride in 70 ml of dichloromethane was added dropwise to a solution of 50.0 g (495 mmol) of 4-hydroxypiperidine and 260 ml of pyridine in 260 ml of dichloromethane at 0° to 15° C. The mixture was stirred at room temperature for 3 h and white crystals (pyridine hydrochloride) thus precipitated were filtered out. The filtrate was concentrated and a remaining oil was purified by silica gel column chromatography (CHCl3 :CH3OH=95:5) to give 79.8 g (yield: 79%) of the intended compound:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[CH3:24]N(C)C=O>>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:24][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Brc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Yield: 100 %

Procedure:
Add sodium hydride (4.89 g, 122.4 mmol, 60% dispersion in mineral oil) to a solution of 4-Bromo-1H-indole (12 g, 61.2 mmol) in dimethylformamide (100 ml). Cool the reaction to 0° C. and add (2-bromoethoxy)-tert-butyldimethylsilane (17.04 g, 67.32 mmol). Stir the reaction for 1 hour at room temperature, quench with aqueous saturated sodium bicarbonate, and extract into ethyl acetate. Combine the organic layers and wash with saturated aqueous sodium chloride, dry over magnesium sulfate. Concentrate under reduced pressure to obtain the title compound, (22.45 g, 100%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) 7.48 (d, J=8, 1H), 7.4 (d, J=3 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.05 (dd, J=8, 1 Hz, 1H), 6.4 (d, J=3 Hz, 1H), 4.25 (t, J=7 Hz, 2H), 3.49 (t, J=7 Hz, 2H), 1.9 (quintuplet, 2H), 0.82 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:7]4[CH:8]=[CH:9][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 36.8 %

Procedure:
A mixture of 4-methanesulfinyl-phenol (Combi-Blocks Inc, San Diego, Calif., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-methanesulfinyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 36%) as a white solid. Mass spectrum MH+=458.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.O>ClCCl.C(NC(C)C)(C)C>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: COCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
2 g of 4-hydroxybenzophenone was dissolved in 20 ml dichloromethane and 2.12 ml diisopropylamine, and then stirred with 0.9 ml chloromethyl methyl ether at room temperature for 16 hours. Dichloromethane and water were added to the reaction mixture, which was then extracted with dichloromethane three times, washed with saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give 4-(methoxymethoxy)benzophenone as an oil quantitatively. Yield: 2.44 g.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:37]=[CH:36][C:8]([C:9]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:10])=[CH:7][CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:16]=3)[CH:11]2[C:9](=[O:10])[C:8]2[CH:36]=[CH:37][C:5]([O:4][CH2:3][CH2:2][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][NH:38]3)=[CH:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: C1CCNCC1
Reactant: O=C(c1ccc(OCCBr)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCC2CCCCN2)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Yield: 73.6 %

Procedure:
A solution of 1-[4-(2-bromethoxy)benzoyl]-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.80 g, 1.43 mmol) and piperidine (0.86 g, 10.1 mmol) in dimethylformamide was stirred at room temperature for 3 hours. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified by chromatography (SiO2, ethyl acetate and 3-5% methanol/ethyl acetate) to provide the title compound (0.594 g, 74% yield): 1H NMR (CDCl3) 8.00 (m, 2H), 7.40 (m, 4H), 6.79-6.92 (m, 10H), 5.87 (s, 1H), 5.02 (s, 2H), 4.15 (t, 2H), 3.72 (m, 1H), 3.48 (m, 1H), 3.07 (m, 1H), 2.79 (t and m, 3H), 2.51 (m, 4H), 1.61 (m, 4H), 1.46 (m, 2H); ES-MS (m/z) 565 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[N:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C(Cl)(Cl)Cl.CO.ClCCl>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:14][C:13]=2[N:26]([CH:27]2[CH2:29][CH2:28]2)[C:35]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2nc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)CC1
Yield: 70 %

Procedure:
Following the procedure of Example K-2, the reaction of N-benzyloxy-2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxamide (Example J-2, 160 mg, 0.42 mmol) with CDI (135 mg, 0.83 mmol) in chloroform (2 mL) and purification of the reaction mixture by flash chromatography on a silica gel with 5% of MeOH/dichloromethane as eluent provided 125 mg of the title compound as powder, mp 188-189° C.