Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:23][CH2:22]1)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidine (1.03 g) obtained in Example 8b) in dimethylformamide (5 mL) were added potassium carbonate (276 mg) and bromoacetic acid ethyl ester (223 μL). The mixture was stirred overnight at ambient temperature of 90° C., and then concentrated in vacuo. The residue was distributed with water and chloroform, and the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, concentrated in vacuo and purified by column chromatography on silica gel with chloroform:methanol=30:1 to give the title compound (598 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([C:10]1[C:11]2[NH:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][N:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1nccc2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A solution of Example 1 (25 mg, 0.1 mmol) in dimetylformamide (DMF; 2 ml) was treated with 0.10 ml of 1M aqueous NaOH (0.10 mmol). After stirring at RT for 30 minutes, acetic anhydride (0.010 ml, 0.095 mmol) was added and reaction stirred 18 h at RT. The reaction was partitioned in EtOAc and 5% citric acid and the organic layer washed with water, dried (brine; MgSO4), and concentrated to give 23 mg of crude product. The crude product was chromatographed (7:3 hexane-acetone) on silica gel to give 10 mg of 1-acetyl-7-bromo-β-carboline.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([C:39]([F:42])([F:41])[F:40])=[O:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:42][C:39]([F:40])([F:41])[S:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1)=[O:38]
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with water, 10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) to yield 99 mg colorless powder that was further purified by HPLC-MS.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]4)[N:19]=[N:20][C:21]=3[C:22]([NH2:24])=[O:23])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:41]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([Cl:51])=[O:50])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>CN1C(=O)CCC1>[C:41]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([NH:25][C:18]3[N:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])=[CH:10][CH:11]=4)[N:17]=3)[CH2:27]2)=[O:50])=[CH:52][CH:53]=1)([CH3:44])([CH3:42])[CH3:43].[ClH:51]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1nnc(N[C@@H]2CCCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)N2CCC[C@@H](Nc3nnc(C(N)=O)c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)C2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide (75) HCl salt (60 mg, 0.13 mmol) in NMP (3 mL) was added DIEA (90 μL, 0.76 mmol) and then 4-tert-butylbenzoyl chloride (39 mg, 0.20 mmol). The mixture was stirred at RT for 20 min, quenched with TFA (0.1 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to afford the title compound (76) as an HCl salt. MS found for C31H38N8O4 as (M+H)+ 587.2, (M−H)− 585.2. UV: λ=268, 287 nm.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14](Cl)=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][NH:28]2)=[O:26])=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl.O.C(Cl)Cl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]2[CH2:31][CH:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:29][N:28]2[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:13]=2)=[O:15])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1
Reactant: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)c1ccnc(Oc2ccccc2)n1
Reaction time: 18 h
Yield: 23 %

Procedure:
2-Phenoxypyrimidine-4-carbonyl chloride, 18, (0.07 g, 0.28 mmol) in methylene chloride (1.5 mL) is added dropwise to a suspension of 2-(4-fluorophenyl)-1-(4-morpholin-4-yl-pyrazolidin-1-yl)ethanone, 13, (0.06 g, 0.18 mmol) in a 2:5 water/CH2Cl2 solution (7 mL) containing NaOH (0.0112 g, 0.28 mmol) at room temperature. The solution is stirred 18 hours and diluted with additional 2:5 water/CH2Cl2. The layers are allowed to separate and the aqueous phase extracted with additional methylene chloride. The organic layers are combined, dried, filtered and concentrated in vacuo to afford a tan solid which is purified by preparative HPLC to provide 0.021 g (23% yield) of the desired product as an oily solid.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:3]=1
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.4 %

Procedure:
To a suspension of thionicotinamide (30.0 g, 217.1 mmol) in EtOH (400 mL) at room temperature was added ethyl bromopyruvate (90% technical, 30.6 mL, 219 mmol). The reaction mixture was heated to reflux and stirred for 2.5 days. The reaction mixture was cooled to room temperature and the precipitate that formed upon cooling was collected via vacuum filtration. The cake was rinsed twice with hexanes. This solid was added to a separatory funnel containing ethyl acetate and saturated aqueous NaHCO3. The biphasic mixture was separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified using silica gel chromatography, (0 to 100% ethyl acetate/hexanes) to afford the desired product as a tan solid (24.1 g, 47%): mp 73-75° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (dd, J=2.6, 1.0 Hz, 1H), 8.69 (dd, J=4.6, 1.6 Hz, 1H), 8.34 (dt, J=7.9, 1.6 Hz, 1H), 8.22 (s, 1H), 7.41 (ddd, J=7.9, 4.6, 1.0 Hz, 1H), 4.47 (q, J=6.9 Hz, 2H), 1.43 (t, J=6.9 Hz, 3H); ESIMS m/z 236.1 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(F)c(F)c1
Temperature: 110 °C
Yield: 35.1 %

Procedure:
(1S)-1-(3,4-Difluorophenyl)ethanamine (977 mg, 6.2 mmol) and 2,6-dichloropyrazine (1.236 g, 8.3 mmol, 1.3 eq) was dissolved in dioxane (5 mL) and potassium carbonate (1.73 g, 2.0 eq) added to the solution. The mixture was then heated at reflux (110° C.) under a nitrogen atmosphere for 65 hours. The crude reaction mixture was then poured onto cold water (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic extracts were concentrated and subjected to flashmaster chromatography (20 g silica cartridge (8:2 petroleum spirits:ethyl acetate, followed by ethyl acetate flush) to afford the desired pyrazine-adduct as an off-white solid (587 mg, 35%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH2:26]([C:28]1[O:29][CH:30]=[CH:31][C:32](=[O:35])[C:33]=1[OH:34])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[NH:8][C:6]1[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:2]([O:34][C:33]2[C:32](=[O:35])[CH:31]=[CH:30][O:29][C:28]=2[CH2:26][CH3:27])[N:7]=1
Reactant: CCc1occc(=O)c1O
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1occc(=O)c1Oc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 133 (0.3 g, 0.78 mmol), 2-ethyl-3-hydroxy-4H-pyran-4-one (0.11 g, 0.78 mmol) and K2CO3 (0.54 g, 3.91 mmol) in dimethylformamide (15 mL) was stirred at 80° C. for 6 hours under nitrogen atmosphere. After completion of the reaction the mixture was cooled to 25° C. and diluted with water (50 mL). The precipitated solid was filtered off and dried under vacuum to afford the title compound E19 as an off-white solid (0.2 g, 52%). mp 124–126° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns 50:50 [0.01 M KH2PO4 (0.1% TFA): CH3CN], 223 nm, Rt 18.47 min, 98.18% purity); MS (CI): m/z 486 (M+, 100), 382 (90).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.C[Si](C=[N+:26]=[N-:27])(C)C.O.NN>CO.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:26][NH2:27])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: NN
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 1 h

Procedure:
50 mg (0.17 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid [preparation according to WO 2007/134862 Example 88A] were dissolved in 0.4 ml of methanol and diluted with 0.6 ml of toluene, and 128 μl (0.26 mmol) of trimethylsilyldiazomethane solution (2 M in hexanes) were then added dropwise until a slight yellow color remained. The reaction was stirred for 1 h and then evaporated to dryness. The residue was taken up in 1 ml of ethanol, 43 mg (0.85 mmol) of hydrazine hydrate were added and the mixture was stirred under reflux for 2.5 h. After cooling, the solution was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 54 mg (96% of theory) of the title compound in a purity of 93% as a colorless solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][SiH2:10][Cl:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:1]([Si:10]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([Cl:11])[Cl:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCC=C
Reactant: Cl[SiH2]Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCCC=C[Si](Cl)(Cl)C=CCCCCCC
Reaction time: 120 h
Yield: 90 %

Procedure:
To a 100 ml glass ampoule equipped with a magnetic stirring bar was added hexachloroplatinic acid (0.15 ml, 0.090M solution in isopropanol). After the solvent was removed under reduced pressure, 1,7-octadiene (14.39 g, 130.6 mmoles) and dichlorosilane (2.08 g, 20.82 mmoles) were condensed in vacuo into the ampoule. The ampoule was sealed off, placed in an oil bath, and heated gradually to the final reaction temperature of 60° C. at which it was kept for 120 hours. After opening the ampoule into a vacuum line and observing no condensibles, the excess 1,7-octadiene was distilled off to yield 6.02 g (90.0% yield) of bis(octenyl)dichlorosilane. Step (b)
Reaction SMILES: [N:1]1OC([O-])=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][N+:5]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>C1(C)C=C(C)C=C(C)C=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:4]3[CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[N:1]=2)=[CH:16][CH:17]=1
Reactant: [O-]c1on[n+]2c1CCCC2
Reactant: Fc1ccc(C#Cc2ccncc2)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: Fc1ccc(-c2nn3c(c2-c2ccncc2)CCCC3)cc1
Temperature: 165 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
A mixture of 1.64 g (11.1 mmol) of 4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium 3-olate and 2.19 g (11.1 mmol) of 4-{[4-fluorophenyl]ethynyl}pyridine in 40 ml of mesitylene is stirred under argon at 165° C. for 16 h. After cooling, the reaction mixture is concentrated under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 888 mg (27%) of the desired product; log P(HCOOH): 1.03; 1H-NMR (CDCl3-d1): 8.52 (d, 2H), 7.38 (dd, 2H), 7.08 (d, 2H), 7.00 (dd, 2H), 4.25 (dd, 2H), 2.85 (dd, 2H), 2.12 (m, 2H), 1.92 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].[OH-:21].[K+].O.[CH3:24]O>ClCCl>[CH3:24][O:21][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20]
Reactant: CO
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCN1CC(C)=C(OC)C2=C1N1CN(OC)C=C1C=N2

Procedure:
1.5 g of intermediate A1 are dissolved in a mixture of 15 ml methanol and 15 ml dichloromethane. 1 g of solid KOH is added. The mixture is heated up to reflux for 7 hours. At room temperature 30 ml water are added. The organic layer is separated. The aqueous layer is extracted with 20 ml dichloromethane. The unified organic layers are washed with 2×20 ml water. The solvent is removed completely. The residue is purified by LC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1Cl.[F-:35].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1[F:35]
Reactant: [F-]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1F
Temperature: 130 °C
Reaction time: 10 h
Yield: 19.8 %

Procedure:
To a solution of N-(2-bromo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-chloro-3-nitrobenzamide 4.89 g (8.27 mmol) in 50 ml of anhydrous DMF was added 2.40 g (41.3 mmol) of potassium fluoride (spray-dried product) under a flow of nitrogen, followed by stirring at 130° C. for 10 hours. Liquid separation was carried out by adding ethyl acetate, hexane, and water to the reaction mixture, and then the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1) to prepare 0.940 g (yield 20%) of a target compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][NH:33][CH:34]6[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a suspension of aldehyde 47 (0.3 g, 0.669 mmol) in a mixture of DCM (9 mL) and DMF (3 mL) were added 4-amino—Boc-piperidine (0.27 g, 1.34 mmol) and acetic acid (80 μL, 1.34 mmol) at RT. The reaction mixture was stirred for 1.5 hr, treated with NaBH(OAc)3 (0.425 g, 2.00 mmol) and stirred overnight, then quenched by addition of saturated NaHCO3 solution and extracted with DCM/MeOH. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/MeOH: 93/7 to 84/16) to afford title compound 607 (0.355 g, 84% yield) as a pale brown solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.58 (brs, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H), 7.72 (dd, J=13.5, 1.8 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.64 (d, J=5.4 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H), 3.85-3.75 (m, 2H), 3.81 (s, 2H), 2.90-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.45-1.35 (m, 1H), 1.39 (s, 9H), 1.25-1.10 (m, 2H), 0.71-0.62 (m, 2 Hz, 0.48-0.40 (m, 2H).
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Ca+2:6].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].[Ca+2:6].[P:1](=[O:2])([OH:5])([OH:4])[OH:3]
Reactant: O=S(=O)(O)O
Reactant: O=P([O-])([O-])O
Agent: [Ca+2]
Product: O=P(O)(O)O
Product: O=S(=O)([O-])[O-]

Procedure:
Means are also provided for reacting the monocalcium phosphate in the liquor with sulfuric acid to produce calcium sulfate crystals in a phosphoric acid solution. This can be conveniently carried out in a crystallizer. Finally, additional separating means are provided for separating the calcium sulfate crystals from the phosphoric acid solution.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C=O)c1
Yield: 88 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.22 g, 10 mmol) in anhydrous acetone (50 mL) was treated with K2CO3 (2.76 g, 20 mmol) and MeI (0.9 mL, 15 mmol) at room temperature for 12 hours. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by flash column chromatography (0-15% EtOAc in hexanes, 1.2 g, 88% yield). 1H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3H), 7.17-7.21 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.47 (m, 2H), 9.99 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 73.1 %

Procedure:
3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 0.754 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate(290 mg, 0.829 mmol), palladium tetrakistriphenyphosphine(52 mg, 0.045 mmol) and sodium carbonate (192 mg, 1.81 mmol) were mixed with ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give tert-butyl N-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (250 mg, 73%). 1H NMR (DMSO-d6) δ 1.48 (s, 9H),1.88 (m, 2H), 2.10 (m, 2H), 2.24 (m, 5H), 2.92 (m, 2H), 3.69(s, 3H), 4.64 (m, 1H), 7.21 (m, 2H), 7.91 (d, J=8.16 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=454.2, Rt=1.67 min.