Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(F)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(F)cc2)n1

Procedure:
119 mg (65.0%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-fluorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (112.3 mg, 0.431 mmol), 1-(2-fluorophenyl)piperazine (102.22 mL, 0.647 mmol), and NaCNBH3 (274.29 mg, 1.294 mmol).
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:10])=CC=1)([O-])=O.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:50]=[C:49]4[C:44]([CH2:45][CH2:46][NH:47][CH2:48]4)=[CH:43][CH:42]=3)[N:38]=[C:37]([NH2:51])[N:36]=2)[CH2:31][CH2:30]1.C(N(CC)CC)C>C(#N)C.O>[NH2:51][C:37]1[N:38]=[C:39]([C:41]2[CH:50]=[C:49]3[C:44]([CH2:45][CH2:46][N:47]([C:9]([O:11][CH:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]4)=[O:10])[CH2:48]3)=[CH:43][CH:42]=2)[CH:40]=[C:35]([N:32]2[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]2)[N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)OC(C)(C)C)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
tert-Butyl 4-{[(4-nitrophenoxy)carbonyl]oxy}piperidine-1-carboxylate (0.093 g, 0.25 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (0.10 g, 0.23 mmol) and triethylamine (0.13 mL, 0.92 mmol) in acetonitrile (5.0 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product (0.10 g, 79%). Analytic LCMS (M+H)+: m/z=552.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[O:25])[CH2:12][CH2:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.9 %

Procedure:
1.0 g (2.97 mmol) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 20 ml methanol/5 ml acetone in a 100 ml one neck round bottom flask. The suspension is treated with sodium meta periodate (666 mg, 3.12 mmole) in 20 ml water and the reaction mixture is stirred 48 hours at room temperature. The organics are removed in vacuo and the aqueous residue is filtered to remove a fine white solid. The solid is washed with water followed by diethyl ether to give 902 mg the title compound) as a solid. mp=204-205° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.I[CH2:21][CH3:22].[BH4-].[Na+]>C(O)C>[CH2:21]([N:17]1[CH2:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3([CH3:13])[O:9][CH2:10][CH2:11][O:12]3)[C:2]=2[F:1])[CH2:19][CH2:18]1)[CH3:22]
Reactant: CC1(c2cccc(-c3ccncc3)c2F)OCCO1
Reactant: CCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CC=C(c2cccc(C3(C)OCCO3)c2F)CC1

Procedure:
Preparation according to preparation 6: 4-[2-fluoro-3-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyridine (0.95 g, 3.66 mmol), 1-iodoethane (4 ml), ethanol (40 ml), sodium borohydride (1.0 g, 29.3 mmol). Yield: 0.88 g. MS m/z (rel. intensity, 70 eV) 291 (M+, bp), 276 (94), 219 (29), 110 (46), 87 (29).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.C(O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:25][O:26][C:27]([C:29]1[CH:30]=[CH:31]C(O)=[CH:33][CH:34]=1)=[O:28].C(C(CCCCCC)CO)CCC>>[C:1]([O:10][C:11]1[CH:31]=[CH:30][C:29]([C:27]([O:26][CH2:25][CH:17]([CH2:16][CH2:15][CH2:14][CH3:13])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:28])=[CH:34][CH:33]=1)(=[O:9])[C:2]1[CH:3]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCO
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)c1ccccc1O
Agent: CCCCCCC(CO)CCCC
Product: CCCCCCC(CCCC)COC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Yield: 71.2 %

Procedure:
In place of 25 g of methyl salicylate and 31 g of n-dodecanol in Example 1-6, 25 g of methyl p-hydroxybenzoate and 31 g of 2-butyl octanol were used for preparation in the same manner in Example 1-6 to obtain 48 g of 2-butyloctyl p-benzoyloxybenzoate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@H:17]([CH3:19])[C@@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CCCC1C2C3OC(C)(C)C=CC=3C3O[C@@H](C)[C@H](C)[C@@H](O)C=3C=2OC(=O)C=1.C([O-])(=O)C.C(=O)([O-])N>CCCCCC.C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)[C@@H]3O
Agent: CC(=O)[O-]
Agent: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Agent: NC(=O)[O-]
Solvent: CCCCCC
Solvent: CCO
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic (±)-1 was resolved into enantiomers, (+)-calanolide A and (−)-calanolide A, by preparative HPLC66. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., PA, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexanelethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 minutes and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amnylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms of (±)-calanolide A and its optical forms are shown in FIG. 1.
Reaction SMILES: [C:1]([N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7])(=O)C.C(N)(=O)C.[P:17]([OH:20])([OH:19])[OH:18].C=O>Cl>[P:17]([CH2:1][N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7])([OH:20])([OH:19])=[O:18]
Reactant: OP(O)O
Reactant: CC(=O)N(CC(=O)O)CC(=O)O
Agent: C=O
Agent: CC(N)=O
Agent: Cl
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Yield: 63 %

Procedure:
A crude reaction mixture of N-acetyliminodiacetic acid was prepared from acetamide (5.90 g; 0.10 mol)) by the process described in French Pat. No. 2,523,576. This crude product was dissolved in a 20% aqueous hydrochloric acid solution and the resulting mixture was added to a 250 ml 3-necked flask equipped with an addition funnel and thermometer. Phosphorous acid (8.61 g; 0.105 mol) was added and the solution was heated to a temperature of 106° C.-107° C. When this temperature had been reached, formaldehyde (8.23 g of a 44% aqueous solution; 0.212 mole) was added to the mixture in the flask over a period of 30 minutes. After addition of formaldehyde was complete, the temperature was maintained at 106°-107° C. for an additional period of 3.5 hour. The reaction mixture was concentrated under reduced pressure and a precipitate formed. The product was collected by filtration to yield 14.4 g of N-phosphonomethyliminodiacetic acid (63% yield based on the starting amount of acetamide).
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][CH2:14][C:15]1[C:16]([O:28]CC[Si](C)(C)C)=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:28][C:16]1[C:15]([CH2:14][CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:10])[OH:6])=[C:23]([O:24][CH3:25])[C:22]([CH3:26])=[C:21]2[C:17]=1[C:18](=[O:27])[O:19][CH2:20]2
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCOCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CCOCP(=O)(O)O)C(=O)OC2
Reaction time: 18 h

Procedure:
To a solution of {2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonic acid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and 2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL, 0.21 mmol) at room temperature. The reaction was allowed to proceed for 18 hours when completion of the reaction was indicated by LCMS. The reaction was quenched by addition of MeOH and concentration. The residue was purified by RP-HPLC using a C18 column. The collected product was dissolved in a solution of 10% TFA/CH2Cl2 to assure complete deprotection. The reaction mixture was lyophilized to provide the desired product. 1H NMR (300 MHz, CD3OD) δ 2.12 (s, 3H), 2.98 (t, 2H, J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H) ppm; MS (m/z) 331 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (126 g, 0.59 mol) in DMF (1.0 L) was added sodium carbonate (249 g, 2.34 mol) and methyl iodide (145 mL, 2.34 mol). The reaction mixture was heated at 60° C. for 4 h. On completion, the reaction mixture was filtered and the residue washed with DCM. The aqueous phase was separated and extracted with DCM. The combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica eluting with ethyl acetate:hexane to afford the title compound (85 g, 63%). 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (d, 1H), 8.05 (s, 1H), 3.9 (s, 1H), 2.4 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])[C:9](=[O:18])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:7]=1)=O)C.C([O-])(=O)C.[NH4+:27]>CO>[C:19]([N:8]1[C:9](=[O:18])[N:10]2[CH:11]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[NH:27][C:4](=[O:3])[C:6]2=[N:7]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(C(C)(C)C)c(=O)n1CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A solution of 8.60 g of the product of Step C and 21.30 g of ammonium acetate in MeOH was heated in a sealed system at 100° C. for 24 h. The solution was cooled to ambient temperature and concentrated to leave an oil that was partitioned between EtOAc and water. The aqueous layer was acidified to pH 5 with concentrated HCl and then extracted with EtOAc. The combined organic layers were washed with sat. sodium chloride, dried over sodium sulfate, filtered, and concentrated to provide 2,6-di-tert-butyl-2H,7H-[1,2,4]triazolo[4,3-a]pyrazine-3,8-dione as a white solid. MS (M+H+)=265.3.
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:6][C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH:11]=1)[C:9]#N.Cl.[CH2:24]([OH:26])C>>[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:6][C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH:11]=1)[C:9]([O:26][CH3:24])=[O:1]
Reactant: CC(C)Oc1nc(-c2ccc(F)cc2)c(Br)cc1C#N
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2)nc1OC(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
An 8 M aqueous potassium hydroxide solution (22.1 mL) was added to a mixture of 5-bromo-6-(4-fluorophenyl)-2-isopropoxynicotinonitrile (5.92 g) and ethanol (50 mL), and the resultant mixture was stirred overnight at 100° C. The reaction mixture was neutralized with 6 M hydrochloric acid at 0° C., followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. Potassium carbonate (4.88 g) and iodomethane (1.66 mL) were added to a mixture of the obtained residue and DMF (30 mL), and the mixture was stirred at 60° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.65 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH2:18]([Mg]Br)[CH3:19]>>[OH:14][CH:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:15]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH2:18][CH3:19]
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Product: CCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12

Procedure:
The compound of Example 115 was reacted with ethyl magnesium bromide as in Example 134 to afford the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][CH2:17]Cl>C(#N)C.O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH2:15][O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COCOc1cccnc1F
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Fluoropyridin-3-ol (55 g, 486 mmol) and cesium carbonate (158 g, 486 mmol) were suspended in ACN (400 mL). A solution of chloromethyl methyl ether (40 mL, 527 mmol) in dry tetrahydrofuran (50 mL) was added dropwise via an addition funnel. After 1 hour additional MOM-Cl (5 mL) was added and the reaction stirred for another 2 h. The reaction was evaporated to dryness under reduced pressure and the residue partitioned between diethyl ether (400 mL) and water (500 mL). The organic was washed with saturated sodium bicarbonate (100 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to 1:1 hexane:DCM gradient) to give the desired 2-fluoro-3-(methoxymethoxy)pyridine (53.5 g, 340 mmol, 70.0% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:41])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3ccccc3)CC2)cc1

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-phenylmethanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate F1) with benzoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.98-2.10 (m, 4H), 3.30 (methyl sulfonyl and water peak), 3.70-3.75 (m, 1H), 4.58-4.63 (m, 1H), 5.14-5.17 (m, 1H), 7.42-7.52 (m, 5H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=478.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29](O)=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:29]([C:24]1[C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:27][N:26]([CH3:28])[N:25]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Yield: 95.2 %

Procedure:
The title compound (3.96 g) was prepared from (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl carboxylic acid (2.20 g) according to the method of D40.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[OH:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:23]3[CH:22]=[C:21]([CH2:20][OH:19])[O:25][N:24]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(CO)on1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CO)on1
Yield: 1.9 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(hydroxymethyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.675 mmol) and 5-(hydroxymethyl)isoxazole-3-carboxylic acid (126 mg, 0.878 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase) and triturated using diethyl ether. Yield 1.9%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 4.28-4-43 (m, 2H), 4.52-4.63 (m, 1H), 4.68 (d, 2H), 6.57 (t, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.07 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: OB(O)c1ccc(O)cc1
Product: Nc1ncc(-c2ccc(O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-hydroxybenzene-boronic acid gives “A72”; method 1: HPLC/MS: 1.07 min, [M+H]=307;
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]([C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:19]([C:26]1[N:31]=[CH:30][C:29]([NH:32][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 6-phenoxypyridine-3-amine as the starting materials.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:26])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:18]
Reactant: CN(C)CCNS(=O)(=O)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)Cc1ccccc1

Procedure:
Prepared from 1-fluoro-4nitro-benzene, N-(2-dimethylamino-ethyl)-C-phenylmethanesulphonamide and sodium hydride as base
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(I)cc2)CC1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
4-Iodobenzoic acid (500 mg, 2.02 mmol) and DMF (50 uL) were dissolved in DCM (24 mL), oxalyl chloride (0.18 mL, 2.12 mmol) was added drop-wise and the reaction mixture was stirred for 30 min. DIPEA (0.42 mL, 2.42 mmol) and a solution of N-methylpiperazine (222 mg, 2.22 mmol) in DCM (1 mL) were added and the reaction mixture was stirred for 30 min, washed with sat aq NaHCO3 (2×75 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (660 mg, 99.2%) as a yellow solid. LCMS (ES+): 331.0 [MH]+. HPLC: Rt 4.05 min, 99.6% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:32]1([P:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C1C=CC=CC=1>[Br-:18].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][P+:38]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1ccc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 4 h
Yield: 76 %

Procedure:
Bromination of 1-chloro-4-methoxy-2-methylbenzene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 4 h, gave the phosphonium salt (578) (76%) as a light brown solid, mp (CH2Cl2/benzene) 189–190.5° C. 1H NMR (CDCl3) δ 7.82–7.61 (m, 15H), 7.21 (t, J=2.8 Hz, 1H), 7.04 (dd, J=8.8, 0.8 Hz, 1H), 6.76 (dt, J=8.9, 2.7 Hz, 1H), 5.59 (d, J=14.4 Hz, 2H), 3.58 (s, 3H). Found: C, 62.75; H, 4.70. C26H23BrClOP requires-C, 62.73; H, 4.66.