Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.[CH3:40][OH:41]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:34])=[O:35])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:40]([NH:5][CH:6]([CH3:11])[CH3:7])=[O:41]
Reactant: CO
Reactant: CC(C)(c1cc(-c2ccc(F)c(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: ClCCl
Product: CC(C)NC(=O)N(Cc1cc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)ccc1F)c1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared in two steps according to the procedures described in EXAMPLE 41 but using the {2-fluoro-5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyl}-(4-methanesulfonyl-phenyl)-amine from present Step 4 as the starting material. Flash chromatography (CH2Cl2:MeOH; 96:4) afforded the compound as a foam.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>O1CCCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 0.347 g, 1.1 eq) was added to a stirred solution of 2-bromo-N-(ethoxycarbonyl)-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide (4.41 g, 10.5 mmol) in anhydrous tetrahydrofuran (150 mL) at room temperture under a dry nitrogen atmosphere. After 1 hour, the t-butyl bromoacetate (2.54 mL, 1.5 eq) was added and the reaction was heated to 55° C. After 11/2 hours of heating, the reaction was cooled to room temperature and the THF was removed. The residue was suspended in ether (250 mL), washed with water (2×100 mL) and saturated aqueous NaCl (1×50 mL), dried with magnesium sulfate, and the ether was removed. The resultant oil was triturated with petroleum ether (1×50 mL) to provide the title compound as a white powder (4.78 g, 85%). A small samle was recrystallized in ether-petroleum ether to provide white crystals for analysis, m.p. 109.5°-112° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:32])[CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:19])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:25]([C@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17]/[CH:16]=[CH:15]/[CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:32])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)C/C=C/CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)C/C=C/CC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 600 mg (1.33 mmol) (E)-(R)-1-[6-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-6-oxo-hex-3-enoyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 15 ml dichloromethane at 0° C. was added dropwise 4.4 ml (57.8 mmol) trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded 402 mg (90%) of the title compound as a white foam. MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]1([CH3:25])[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([CH3:24])[C:20](OC)=[O:21])[CH:14]=1>O1CCCC1>[O:21]=[C:20]([C@@H:19]([C:15]1[CH:14]=[C:13]([CH3:25])[CH:18]=[CH:17][CH:16]=1)[CH3:24])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)[C@H](C)c1cccc(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@H](C)c1cccc(C)c1)OC
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To dimethyl methylphosphonate (1.97 g) was added tetrahydrofuran (THF) (25 mL), and the mixture was cooled to −78° C. n-Butyllithium (1.5 M hexane solution) (10 mL) was added, and the mixture was stirred for 1 hr. Then, a solution of methyl ester {methyl (2R)-2-(m-tolyl)propionate} synthesized in Example 1 (1.34 g) in THF (3.8 mL) was added at −78° C., and the mixture was stirred for 2 hr. The reaction was quenched with 25 mL of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5:1-1:5) to give the title compound (1.63 g). The structural property was as described below.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([F:2])[CH:8]=1)=[S:21]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NCc1ccnc(F)c1
Agent: Cl
Product: Fc1cc(CNC(=S)Nc2cccc(Cl)c2Cl)ccn1
Yield: 53 %

Procedure:
Prepared in 53% yield from the product of Example 143A and 2,3-dichlorophenylisothiocyanate according to the procedure described for Example 141B. MS (ESI+) m/z 329.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.79 (d, J=5.8 Hz, 2H), 7.02 (br s, 1H), 7.26 (d, J=5.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.48-7.61 (m, 2H), 8.18 (d, J=5.1 Hz, 1H), 8.43 (br s, 1H), 9.69 (br s, 1H).
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=1)(=[O:22])[CH3:21]
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCc1ccc(NC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 1-liter flask fitted with a stirrer and reflux condenser is added 137.5 grams (0.525 mole) of p-n-dodecylaniline, dissolved in 138 ml of tolune. To this is added over a 15-minute period 57.5 ml of acetic anhydride. The temperature rises from 40° to 80° C. After all the acetic anhydride is added, the reaction mixture is stirred at 40° C. for 3 hours. The reaction mixture is then cooled to yield the crude product which is recrystallized from 800 ml of methanol to give 151.1 grams of the above-named material as a solid melting at 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=O)[C:8]=1[CH2:9][C:10]([OH:12])=O.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([N:19]1[C:10](=[O:12])[CH2:9][C:8]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:13]1=[O:15])[CH:17]=[CH2:18]
Reactant: COc1cccc(C(=O)O)c1CC(=O)O
Reactant: C=CCN
Product: C=CCN1C(=O)Cc2c(OC)cccc2C1=O

Procedure:
A mixture of 6-methoxyhomophthalic acid (9.7 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) is heated by an oil bath until molten for 40 minutes. The mixture solidifies upon cooling and is recrystallized from isopropanol, giving 2-allyl-5-methoxyisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[O:5]1.I[CH2:22][CH3:23]>C1COCC1>[CH2:22]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([B:6]3[O:5][C:4]([CH3:20])([CH3:3])[C:8]([CH3:9])([CH3:10])[O:7]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:23]
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Temperature: 0 °C

Procedure:
To a 0° C. suspension of NaH (43 mg, 1.81 mmol) in THF (4 mL) was added a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (400 mg, 1.65 mmol, Aldrich) in THF (4 mL). The reaction mixture was maintained at 0° C. for 15 min, iodoethane (0.200 mL, 2.47 mmol) was added and the reaction was heated, at 50° C. for 30 min. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 1-8% EtOAc/hexanes afforded the title compound as a white solid. LC-MS: calculated for C16H22BNO2 271.16, observed m/e 273.2 (M+H)+ (Rt 2.09 min).
Reaction SMILES: Cl.COC[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>C(O)C>[F:31][C:29]([F:30])([F:32])[O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][CH2:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=3)[CH2:17][CH2:16]2)=[CH:27][CH:26]=1
Reactant: COCOc1ccc(N2CCC(CCOCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(N2CCC(CCOCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
6 N hydrochloric acid (1 ml) was added to an ethanol solution (15 ml) of 1-(4-methoxymethoxyphenyl)-4-[2-(4-trifluoromethoxybenzyloxy)ethyl]piperidine (1.51 g) and stirred at 60° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a pink solid (1.34 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([OH:10])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:6][C:5]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: C1=COCCC1
Reactant: OCc1cc(O)c(F)cc1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Fc1cc(Br)c(COC2CCCCO2)cc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 83 %

Procedure:
Protection of the alcohol was carried out by making a solution of 4-bromo-2-fluoro-5-(hydroxymethyl)phenol (1.37 g, 6.19 mmol), 3,4 dihydro-2H-pyran (1.4 mL, 15 mmol) in 20 mL of CH2Cl2. The reaction mixture was then treated with camphor sulfonic acid (58 mg, 0.25 mmol) before stirring at room temperature for 21 hr. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 20 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-(4-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.0 g, 83%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29](SC)[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([Cl:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:51][NH2:52].C1COCC1>>[C:1]([N:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[C:35](=[O:36])[N:34]([CH3:37])[C:27]4[N:28]=[C:29]([NH:52][CH3:51])[N:30]=[CH:31][C:26]=4[CH:25]=3)[C:21]([Cl:38])=[CH:20][C:19]=2[F:39])=[O:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3Cl)c(=O)n(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4C(F)(F)F)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 56 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (230 mg, 0.394 mmol), MCPBA (126 mg, 0.512 mmol) and 2.0N methylamine in THF (1.97 mL, 3.94 mmol) were combined to afford 1-(1-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (127 mg, 56% yield). 1H NMR (300 MHz, DMSO-d6), δ 1.59 (s, 9H), 2.92 (s, 3H), 3.53-3.62 (m, 3H), 7.55-7.65 (m, 1H), 7.78 (s, 1H), 7.80-7.90 (m, 1H), 7.93 (s, 1H), 8.15-8.25 (m, 1H), 8.45-8.70 (m, 2H), 9.25 (s, 1H); MS (ESI) m/z: 567.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:10]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 2-trifluoromethoxy benzoic acid [1979-29-9] (1.0 g) was added in small batches to chlorosulfonic acid (3.2 mL) at 0° C. After completion of the addition, the reaction mixture was stirred at 70° C. for 4 hours then left at room temperature overnight and heated at 75° C. for another 3 hours. After such time the reaction was slowly poured onto ice, and the precipitate was then filtered, washed with water and dried to yield the title compound as a white solid (1.2 g). MS (m/e): 303.3 (M−H, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([CH3:8])[CH2:6][CH3:7])[CH2:3][OH:4]>[Ru].O1CCOCC1>[CH:5]([CH:2]1[NH:1][C:3](=[O:4])[CH:2]([CH:5]([CH2:6][CH3:7])[CH3:8])[NH:1][C:3]1=[O:4])([CH2:6][CH3:7])[CH3:8]
Reactant: CC[C@H](C)[C@H](N)CO
Agent: [Ru]
Solvent: C1COCCO1
Product: CCC(C)C1NC(=O)C(C(C)CC)NC1=O
Yield: 72 %

Procedure:
Upon refluxing a dioxane solution containing 2 mmol of (2S,3S)-2-amino-3-methylpentan-1-ol and 0.02 mmol of catalyst 1 for 19 hrs and cooling the reaction mixture, the solid product precipitated and was filtered off and dried under vacuum to give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7c in 72% yield (Table 9, entry 2). The structure was confirmed by NMR and MS spectroscopies. Under the same conditions, cyclic peptidation of (S)-2-amino-3-methylbutan-1-ol led to 3,6-diisopropylpiperazine-2,5-dione 7d as an insoluble solid which separated from the reaction mixture and was isolated by filtration and dried under vacuum to give 78% of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7d (Table 9, entry 3). The optical rotation of the pure product (−52°) was essentially the same as reported in the literature (−) 54°. Thus, under these experimental condition, no racemization took place.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]5[NH:27][N:28]=[CH:29][C:22]=45)[CH2:17][CH2:16]3)[N:12](C)[CH:13]=2)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31].[Cl:34][CH2:35]Cl>>[ClH:34].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:35])[CH:11]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:26]=[CH:25][N:24]=[C:23]5[NH:27][N:28]=[CH:29][C:22]=45)[CH2:19][CH2:20]3)[NH:12][CH:13]=2)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31]
Reactant: ClCCl
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3[nH]ncc23)CC1
Agent: Cl
Product: CN1C(c2ccc(F)c(C(F)(F)F)c2)=CNC1C1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.47 %

Procedure:
Add hydrogen chloride (1.1 equiv; 18.52 mmoles; 4.63 mL) to a suspension of 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine (7.5 g; 1.00 equiv; 16.84 mmoles) in dichloromethane (50 mL), and stir the mixture for 1 hour at room temperature. Remove the solvent in vacuo, and triturate the crude in MTBE for 1 hour. Filter the solid and dry in vacuo overnight to give 4-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (7.99 g; 16.58 mmoles; 98.47% yield) as a white solid. 1H-NMR (300 MHz, DMSO): δ14.01-13.99 (m, 1H), 8.57-8.54 (m, 2H), 8.26-8.19 (m, 3H), 7.72-7.63 (m, 1H), 5.23-5.20 (m, 2H), 3.89 (s, 3H), 3.41 (m, 2H), 2.15-2.07 (m, 3H), 1.10 (s, 2H).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].[CH3:16][CH2:17]O>>[CH2:16]([O:14][C:13]([C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:12][NH:11][N:10]=1)=[O:15])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 96 %

Procedure:
Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96%). (1H NMR (400 MHz, DMSO-d6) δ 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).
Reaction SMILES: [NH2:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]>O1CCOCC1>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:1][NH2:2])=[O:21])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: NN
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)Oc1ccccc1
Solvent: C1COCCO1
Product: NNC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Hydrazine (1.18 mol) was added dropwise over a 1 hour period to a solution of intermediate (1) in 1,4-dioxane (1000 ml) and the mixture was stirred and refluxed overnight. The mixture was cooled and filtered off, yielding N-(4-nitro-phenyl)hydrazinecarboxamide (intermediate 2).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:26]([C:24]1[CH:23]=[CH:22][C:21]([O:29][CH3:30])=[C:20]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][NH:8][C:5]2[N:4]=[CH:3][C:2]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[CH:7][N:6]=2)[CH:25]=1)([CH3:28])[CH3:27]
Reactant: C1COCCN1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(N2CCOCC2)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(5-Bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (3.30 g) is dissolved in toluene (30 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (1.26 g), 2-(di-tert-butylphosphino)biphenyl (1.23 g), morpholine (2.4 ml) and sodium tert-butoxide (1.32 g) and the mixture is degassed under reduced pressure and stirred under nitrogen flow at 50° C. overnight. To the reaction mixture is added a saturated brine, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:1) to give (5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (1.11 g). MS (m/z): 487 [M+H]+
Reaction SMILES: [OH:1][CH:2]([CH3:39])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:39])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:22]2[CH2:26][CH2:25][C@H:24]([C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=3)[O:23]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: c1c[nH]cn1
Reactant: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 55 °C
Reaction time: 28 h

Procedure:
A mixture of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(3-bromopropoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (87 mg, 0.14 mmol) (Example 19B), imidazole (47 mg, 0.69 mmol) and potassium carbonate (95 mg, 0.69 mmol) in acetone (2 mL) was heated with stirring at 55° C. under nitrogen for 28 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue. Purification by preparative TLC (CH2Cl2 -MeOH; 9:1, v/v) gave the title compound: Rf 0.6; MS, m/z 618 M+. ; NMR (CDCl3) δ 1.28 (bd, CH2CHOHCH3), 6.94 and 7.08 (bs, NCH=CHN), 7.54 (NCH=N).
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH:12]1([CH2:11][C@H:2]([OH:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
2 (1.02 g, 5.39 mmol, 1 eq) is dissolved in 60 mL of dry DCM and cooled to 0° C. Trichloroisocyanuric acid (1.32 g, 5.65 mmol, 1.05 eq) is added and mixed for 10 minutes resulting in a white slurry. TEMPO is added (8.8 mg, 0.056 mmol, 0.01 eq) to the chilled reaction mixture which immediately turns orange and additional precipitate is formed. The reaction vessel is removed from the cold bath and the mixture is stirred for additional 45 minutes. The reaction mixture is then filtered through a pad of celite, washed with 5% citric acid followed by saturated bicarbonate, dried over MgSO4, filtered, and stripped to yield pure 3 (0.979 g, 97% yield) which was used immediately in step C.