Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O)([F:4])[F:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[S:35]([O:42]S(C(F)(F)F)(=O)=O)([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36]>>[O-:42][S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36].[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[S+:5]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]([F:4])([F:3])[F:1]
Reactant: c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: FC(F)(F)[S+](c1ccccc1)c1ccc(Cl)cc1Cl
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 22 °C
Reaction time: 96 h

Procedure:
2,4-Dichlorophenyl trifluoromethyl sulfoxide (0.71 g, 2.7 mmol), 20 ml of Fréon 113 (stored over P2O5), predistilled benzene (0.57 g, 7.3 mmol) and then triflic anhydride (1.48 g, 5.2 mmol) are introduced into a Schlenck tube placed under an inert atmosphere. The mixture is stirred for 4 days at ambient temperature (22° C.). The purification was not yet appropriate (chromatography on silica with the pentane/ethyl acetate 30/1 mixture as eluent) and did not allow the pure product to be isolated. However, the product is obtained with a crude yield of 74%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[NH2:21].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[NH2:21][C:11]1[C:10]([O:9][CH3:8])=[C:15]([NH:16][S:23]([CH3:22])(=[O:25])=[O:24])[CH:14]=[C:13]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cc(C2(C)CC2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(N)cc(C2(C)CC2)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 50.4 %

Procedure:
Triethylamine (521 mL, 3.74 mmol) was added to a solution of 2-methoxy-5-(1-methyl-cyclopropyl)-benzene-1,3-diamine (718 mg, 3.74 mmol) in methylene chloride at −10° C. Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwise over a 10 min period and the resultant solution was allowed to slowly warm to rt over 2 h. The mixture was quenched with saturated aqueous NaHCO3 and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ammonium hydroxide/35% ethyl acetate in hexanes to 1% ammonium hydroxide/50% ethyl acetate in hexanes) provided a red solid which was triturated with a diethyl ether/hexanes (1:1) to yield Compound 1 (510 mg, 51%) as a pale brown solid: mp 144–146° C. ESI MS (m/z 271, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C1(C)C=CC=CC=1.O>[CH2:25]([O:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:23][CH:24]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1)OCc1ccccc1
Reaction time: 2 h

Procedure:
8 g of 1-[4-aminobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine are dissolved in 200 ml of dioxane. 8.7 g of chloroformic acid benzyl ester in the form of a 50% solution in toluene are added dropwise thereto at 15°. After 2 hours at room temperature, the reaction mixture is diluted with water, dioxane is distilled off and the aqueous phase is rendered alkaline with 2N sodium hydroxide solution and extracted by shaking with ethyl acetate. The oil obtained from the ethyl acetate is crystallised from alcohol and ether, yielding 1-[4-(N-benzyloxycarbonylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 149°-150°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH2:19]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
4-Bromo-1-fluoro-2-nitrobenzene (1.50 g, 6.82 mmol) and K2CO3 (1.88 g, 13.6 mmol) were suspended in DCM (7 mL). MeNH2 (40% in H2O, 7 mL) was added slowly and the mixture stirred at room temperature for 4 h. The mixture was diluted with H2O and extracted with DCM (3×40 mL). The combined DCM layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the product as a bright orange solid (1.47 g, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.3683 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl methane sulfonamide (Intermediate 17), (120 mg, 0.368 mmol) using sodium carbonate (117 mg, 1.1049 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.0184 mmol) in DME/water (15/2 ml). This afforded 107 mg (43.8% yield) after purification by column (Silica gel 230/400) using 65% ethyl acetate in hexane as eluent. MS: m/z=664.1 (M+1).
Reaction SMILES: [NH2:1][C@@:2]12[CH2:7][C@H:6]1[CH2:5][O:4][C:3]2=[O:8].[F:9][C:10]([F:16])([F:15])[CH2:11][C:12](O)=[O:13].OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[F:9][C:10]([F:16])([F:15])[CH2:11][C:12]([NH:1][C@@:2]12[CH2:7][C@H:6]1[CH2:5][O:4][C:3]2=[O:8])=[O:13]
Reactant: N[C@@]12C[C@H]1COC2=O
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(F)(F)F)N[C@@]12C[C@H]1COC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
(±)-Trans-1-amino-3-oxabicyclo[3.1.0]hexan-2-one (128 mg, 1.13 mmol) was mixed with 3,3,3-trifluoropropionic acid in 2.3 mL of N,N-dimethylformamide. Hydroxybenzotriazole (17.4 mg, 0.11 mmol) was added followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (282 mg, 1.47 mmol). The pH of the reaction mixture was adjusted to 8.5 with triethylamine and the mixture was allowed to stir at ambient temperature for 2 hours. Water was then added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate) and concentrated to give the crude product. This was purified by silica gel chromatography to afford 120 mg (45%) of 3,3,3-trifluoro-N-[(±)-trans-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]-propanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)N)=[CH:4][N:3]=1.[CH3:19][NH+:20]1[C@@H:25]2[CH2:26][C:27]([CH2:29][C@H:21]1[CH2:22][CH2:23][CH2:24]2)=O.S(=O)(=O)(O)O>O1CCOCC1>[CH3:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:23]1[CH2:24][CH:25]3[N:20]([CH3:19])[CH:21]([C:22]2=1)[CH2:29][CH2:27][CH2:26]3
Reactant: C[NH+]1[C@@H]2CCC[C@H]1CC(=O)C2
Reactant: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)nc2)CC2CCCC1N2C
Temperature: 80 °C

Procedure:
In a 25 ml, round-bottomed flask were combined 2-chloro-5-(2-(1-p-tolylhydrazinyl)-ethyl)pyridine (50 mg, 0.19 mmol; Example 117D), pseudopelletierine hydrochloride (40 g, 0.21 mmol; Acros), and concentrated sulfuric acid (31 μL) in dioxane (8 mL). The reaction mixture was heated to 80° C. for 6 hours, then cooled to room temperature. The solvent was removed under vacuum and residue was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1% trifluoroacetic acid) over 15 minutes] to afford the title compound as the bistrifluoroacetic acid salt: 1H NMR (300 MHz, methanol-d4) δ ppm 0.94-1.13 (m, 1H), 1.39-1.51 (m, 1H), 1.71-1.80 (m, 1H), 1.91-2.17 (m, 3H), 2.43 (s, 3H), 2.50 (d, J=18 Hz, 1H), 2.66 (s, 3H), 2.96 (dd, J=18, 7 Hz, 1H), 3.14-3.23 (m, 2H), 3.83 (t, J=5 Hz, 1H), 4.41 (t, J=6 Hz, 2H), 4.90 (d, J=2 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 7.24 (s, 1H), 7.32 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.50 (dd, J=8, 2 Hz, 1H), 7.77 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 380 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>>[N+:1]([C:4]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:17]2[C:13](=[N:14][NH:15][CH:16]=2)[NH:12][C:5]=1[CH2:8][CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Nc1cc[nH]n1
Product: CCCC1=C([N+](=O)[O-])C(c2ccccc2[N+](=O)[O-])c2c[nH]nc2N1

Procedure:
The title compound was prepared from n-butylaldehyde, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[O-]CC.[Na+].[Na].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CS(C)=O.C(O)C>[I:1][C:2]1[C:7]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(I)c(O)c1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cnc(I)c(OCc2ccccc2)c1
Yield: 94 %

Procedure:
2-Iodo-3-hydroxy-5-methylpyridine (13.5 g, 57.4 m.mole) was added to a solution of sodium ethoxide (57.4 m.mole, prepared freshly from sodium and dry ethanol (100 ml)). Dry dimethyl sulfoxide (250 ml) was added, and the ethanol was removed by distillation under reduced pressure. Benzyl chloride (7.27 g, 57.4 mole) was added portionwise with cooling and then the mixture was heated at 90°14 100° for 15 hours. The dimethyl sulfoxide was boiled off under reduced pressure, water was added (100 ml) and the product was extracted from this with chloroform. After drying with magnesium sulfate and evaporation under reduced pressure, a crude product was obtained (17.62 g, 94% yield) a tiny portion of which, after heating in water and then recrystallising from methanol-water, gave 2-iodo-3-benzyloxy-5-methylpyridine which was pure by N.M.R. (mp 83°-5°).
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3].[CH3:19]I.[H-].[Na+].O>CN(C)C=O>[CH3:19][O:1][C:2]([CH:5]1[CH2:9][O:8][C:7]([CH3:10])([CH3:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(C(C)(C)O)COC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)C1COC(C)(C)N1C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
tert-Butyl 4-(1-hydroxy-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (Y. Yonezaw et al., Synthesis, 634-636 (2000); 2.6 g) and methyl iodide (1.2 ml) were dissolved in dimethylformamide (20 ml). Sodium hydride (0.59 g) and n-tetrabutyl iodide ammonium (0.72 g) were added thereto at 0° C., and mixed at room temperature for 2.5 days. To the reaction mixture was added water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (2.5 g, 95%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])#[N:3].C(N(C(C)C)C(C)C)C.[C:25](ON=C(C1C=CC=CC=1)C#N)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>O.O1CCOCC1>[C:25]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:13]=[CH:14][CH:15]=[C:4]([C:2]#[N:3])[CH:5]=1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Reaction time: 16 h

Procedure:
6 g (26.5 mmol) of 3-cyano-(L)-phenylalanine hydrochloride and 9.1 ml (53.2 mmol) of N-ethyldiisopropylamine was suspended in 17 ml of water. To this suspension was added a solution of 7.2 g (29.2 mmol) of 2-(Boc-oxyimino)-2-phenylacetonitrile in 20 ml of dioxane and stirring continued for 16 hours at room temperature. After subsequent addition of 50 ml of water, the solution was extracted with 50 ml of ethyl acetate, the organic phase separated and the pH of the aqueous phase adjusted to 3 with dilute hydrochloric acid. After 3 extractions with 100 ml each of ethyl acetate, the collected organic solutions were washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:6]=2[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.ON1C2C=CC=CC=2N=N1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[CH2:37][CH2:36]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:12]([C:11]3[C:6]4[O:5][C:4]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:3][C:2](=[O:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)=[O:13])=[CH:51][CH:50]=1)[CH2:37][CH2:36]2
Reactant: O=C(O)c1cccc2c(=O)cc(-c3ccccc3)oc12
Reactant: COc1cc2c(cc1OC)CN(CCCCc1ccc(N)cc1)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCc1ccc(NC(=O)c3cccc4c(=O)cc(-c5ccccc5)oc34)cc1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid* (1 g) and 1-hydroxybenzotriazole (0.58 g) in DMF (50 ml) was stirred at room temperature for 10 min. 4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine (intermediate 2(d) in EP-A-494623) (1.1 g) was then added, followed by dicyclohexylcarbodiimide (0.67 g) and the mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with methylene chloride. The combined, dried, organic extracts were evaporated and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (99:1) to give the title compound (0.6 g) as a white solid, after crystallisation from ethyl acetate, mp=117°-120°.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-:8])[CH:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCCC1.C[CH:27]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[O:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:11][CH:43]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[O:31][CH2:32][CH2:33][CH2:34][NH:35][C:1]([C:2]2[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:44]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(c1cccc(OCCCN)c1)N1CCCCC1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5 g of 4-dimethylaminopyridine in 80 ml of acetonitrile there is added 5.6 g of nicotinic acid 1-oxide. The mixture is stirred 10 minutes at room temperature and then added with 9.2 g of dicyclohexylcarbodiimide. After standing 5 minutes at room temperature, there are added 10 g of 3-[3-(methylpiperidinomethyl)phenoxy]propylamine dissolved in 20 ml of acetonitrile. A weakly exothermic reaction (from 20° to 25° C.) and a dissolution which within 5 minutes is almost completed, are observed. Then the mixture is stirred 4 hours at 40° C. and the dicyclohexylurea which forms is filtered and washed with acetonitrile. After evaporation to dryness under reduced pressure, the residue is purified by chromatography on silica as described in Example 7. Thus, the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide is obtained, identical to the product of Example 8; m.p. 108°-110° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:3]1.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[Br:15][C:16]1[CH:17]=[C:18]([CH2:19][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[O:5][CH2:6][C:2]([CH3:14])([CH3:1])[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1C1=NC(C)(C)CO1
Reactant: BrCc1cccc(Br)c1
Product: CC1(C)COC(c2ccccc2CCc2cccc(Br)c2)=N1

Procedure:
The subtitle compound was prepared from the product of step (i) (1 g) and 3-bromobenzylbromide (1.32 g) according to the method of example 21 step (ii). Purification was by chromatography eluting with 5-10% ethyl acetate inisohexane. Yield 0.64 g.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][C:10]=2[CH3:14])O1.Cl[C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]2)[CH:20]=[CH:21][CH:22]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C@H:27]1[O:26][C@@H:25]([CH3:30])[CH2:24][N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[CH:13]=[CH:12][O:11][C:10]=3[CH3:14])[CH:18]=2)[CH2:28]1
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(c2cccc(Cl)c2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Temperature: 100 °C

Procedure:
4,4,5,5-Tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane (1.645 g, 7.91 mmol) was added to a solution of cis-4-(3-chlorophenyl)-2,6-dimethylmorpholine (1.785 g, 7.91 mmol) in a mixture of 1,4-dioxane (17 mL), water (2.83 mL) and sodium carbonate (1.676 g, 15.82 mmol). The solution was degassed using argon gas and then charged with tetrakis(triphenylphosphine)palladium(0) (0.914 g, 0.791 mmol). After addition, the reaction mixture was stirred and heated in the microwave at 100° C. for 48 hours. Crude LC/MS showed desired product and only 26% of starting material can be seen. The reaction mixture was washed with ethyl acetate (200 mL), water (100 mL), filtered and then evaporated to dryness. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by using a Biotage SP4 chromatographic system (65i cartridge, eluted with 0-50% ethyl acetate in isohexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a colourless oil (0.74 g, 2.59 mmol, 32.8% yield). LC/MS [M+H]+=272.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]2)[C:17]([F:21])=[CH:16][N:15]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)[C@@H]1CCC[C@H](N)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C

Procedure:
To a solution of (1R,3S)-ethyl 3-aminocyclohexanecarboxylate, 18, (5.1 g, 24.1 mmol) and 2,4-dichloro-5-fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7 g of (1R,3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as a white solid: LCMS RT=3.1 (M+H) 302.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[C:5]2[C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:16])([F:14])[F:15])([OH:17])[CH:11]([NH:22][C:23]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][NH:27]4)[C:6]=2[CH:7]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2cc(Cl)cc(O)c21
Yield: 18.2 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 410 mg of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 168 mg of 4-aminoindazole. 98 mg of the title compound is obtained by reaction of 200 mg of imine with 6.7 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: N1C[CH2:4][C@H:3]([OH:6])C1.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:35]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:19][CH:18]=3)[C:9]=12>>[C:3]([OH:6])(=[O:25])[CH3:4].[C:41]([OH:42])(=[O:6])[CH3:40].[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:35]3[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:36]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]4[O:25][C:26]5[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:27]=5[N:28]=4)=[CH:21][CH:22]=3)[C:9]=12
Reactant: O[C@H]1CCNC1
Reactant: COCCN1CCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Product: CC(=O)O
Product: COCCN1CC[C@@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1

Procedure:
N2-(4-{4-Amino-1-[(3R)-1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine diacetate was prepared from (S)-(−)-3-pyrrolidinol in a manner analogous to that used for the preparation of rac-N2-(4-{4-amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.214 g, 39%). 1H NMR (DMSO-d6, 400 MHz) 1.89 (s, 6H), 2.28-2.31 (m, 2H), 2.35 (s, 3H), 2.40 (s, 3H), 2.65 (t, 2H), 2.73-2.87 (m, 2H), 3.17 (t, 2H), 3.24 (s, 3H), 3.45 (t, 2H), 5.37 (m, 1H), 6.79 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H); RP-HPLC Rt 11.674 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 499 (MH+).