Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C@H:11]2[C:22]([O:24]C)=[O:23])=[N:8][CH:9]=1.[OH-].[Na+]>O>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)[C@H:11]([C:22]([OH:24])=[O:23])[CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a methanol solution of the compound (2.8 g) obtained in step 7 was added a solution of sodium hydroxide (0.7 g) in water (30 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified (pH 5) with acetic acid, extracted with dichloromethane, dried and concentrated under reduced pressure to give (3S,4S)-1-(tert-butoxycarbonyl)-4-(5-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid (2.3 g, 85%) as a white oil.
Reaction SMILES: Cl.[N+]([O-])(OCCC(C)C)=O.[CH3:11][O:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:29]([N:31]=[N+]=[N-])=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])=[CH:15][CH:14]=1.[N-]=[N+]=[N-].[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45](N)[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:41])[CH3:40]>CN(C)C=O.C(N(CC)CC)C>[CH:39]([O:42][C:43](=[O:55])[CH:44]([OH:54])[C@@H:45]([NH:31][C:29](=[O:30])[C@H:22]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:21][C:19]([O:18][CH2:17][C:16]1[CH:34]=[CH:35][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:20])[CH2:46][CH:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1)([CH3:41])[CH3:40]
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N=[N+]=[N-])cc1
Reactant: CC(C)OC(=O)C(O)[C@@H](N)CC1CCCCC1
Agent: CC(C)CCO[N+](=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC2CCCCC2)C(O)C(=O)OC(C)C)cc1

Procedure:
In 15 ml of N,N-dimethylformamide was suspended 1.37 g of the hydrazide compound, and to the suspension were successively added a solution of a 5.95N-dry hydrogen chloride in 2.29 ml of N,N-dimethylformamide and 0.66 ml of isoamyl nitrate with stirring at -20° C. After disappearance of the hydrazide compound, the reaction mixture was cooled to -30° C., and then neutralized by an addition of 1.89 ml of triethylamine to prepare a cold solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added to a solution of 1.00 g of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester in 40 ml of N,N-dimethylformamide with stirring under ice-cooling. The mixture was still stirred for 16 hours, and then the reaction mixture was evaporated under reduced pressure. To the residue was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1) to obtain 1.70 g of (2RS, 3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester as a white powder. In 50 ml of methanol was 1.70 g of the butyric acid isopropyl ester compound, and to the solution were added 10 ml of a 2N hydrochloric acid and 200 mg of a 10% palladium charcoal. The mixture was hydrogenated under an atmospheric pressure. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 1.36 g of (2RS, 3S)-3-(L-histidyl)amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride as a white powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([CH:9]=1)[CH:7]=O.CCCCCCC=CCCC.[F:22][C:23]([F:32])([F:31])/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN1CCCN(C)C1=O>[I:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][CH:24]([C:23]([F:22])([F:32])[F:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7]2
Reactant: Nc1ccc(I)cc1C=O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: CCCC=CCCCCCC
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1=Cc2cc(I)ccc2NC1C(F)(F)F
Temperature: 60 °C
Yield: 50.3 %

Procedure:
A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol), and ethyl 4,4,4-trifluorocrotonate (35.7 g, 212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (48 mL) was heated at 60° C. for 8 hours. The solution was cooled to room temperature and the solution poured into ethyl acetate-hexanes (1:1, 500 mL). The solution was extracted with 2.5 N aqueous hydrochloric acid (2×200 mL), saturated aqueous ammonium chloride (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexanes (100 mL) and fine yellow crystals formed upon standing. Vacuum filtration of this suspension yielded ethyl 6-iodo-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50% yield): mp 137–138° C. 1H NMR (CDCl3, 300 MHz) 7.62 (s, 1H), 7.36–7.48 (m, 2H), 6.43 (d, J=8.2 Hz), 5.36 (brs, 1H), 5.11 (q, 1H, J=7.1 Hz), 4.25–4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz). ESHRMS m/z 395.9716 (M−H, Calc'd 395.9708).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[C:5](F)=[CH:4][N:3]=1.Cl.CN.C([N:26](C(C)C)CC)(C)C>>[CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:26])[N:7]=2)=[CH:10][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Product: CC(C)Oc1ccc(Nc2ccnc(N)n2)cc1

Procedure:
In a like manner to the preparation of N4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine, methylamine hydrochloride, and diisopropylethylamine were reacted to provide 5-fluoro-N2-[2,3-dihydro-2-[N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.92 (s, 1H), 8.06-7.98 (m, 1H), 7.97 (d, 1H, J=4.2 Hz), 7.60-7.52 (m, 3H), 7.20 (d, 1H, J=8.1 Hz), 6.85 (d, 2H, J=8.7 Hz), 6.67 (d, 1H, J=9.0 Hz), 5.04 (dd, 1H, J=5.7 and 9.9 Hz), 4.56 (quintet, 1H, J=6.6 Hz), 3.36 (dd, 1H, J=10.5 and 16.5 Hz), 3.10 (dd, 1H, J=5.7 and 15.3 Hz), 2.59 (d, 1H, J=4.5 Hz), 1.24 (d, 6H, J=6.6 Hz); LCMS: purity: 96%; MS (m/e): 438 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:4]1[N:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=2)[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]=12
Reactant: COc1cccc(Oc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: COc1cccc(Oc2nc(-c3ccc(N)nc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-4-(3-methoxy-phenoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (80 mg) was coupled to 2-aminopyridine-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 47.3 mg of 125. MS (Q1) 349.2 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[N:20]([CH3:34])[N:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][N:15]=[C:16]([C:18]2[C:22]([OH:23])=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=3)[N:20]([CH3:34])[N:19]=2)[CH3:17])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(Br)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 64.6 %

Procedure:
To methyl 2-bromo-4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.455 mmol, 239.8 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.3 mmol, 2.3 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.3 mmol, 2.3 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (203.8 mg). Further, 178 mg of the crude desired product was dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (150.9 mg, yield 74%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=3[F:19])[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Reaction time: 0.08 h
Yield: 34 %

Procedure:
N-[1-{[3-(aminomethyl)phenyl]methyl}-7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 46) (70 mg, 0.15 mmol) was dissolved in DCM (0.75 mL) and triethylamine (0.203 mL, 1.45 mmol) was added to the solution. The solution was stirred for 5 min and acetic anhydride (0.013 mL, 0.13 mmol) was added. The reaction was stirred for 1 h, and then concentrated under a stream of nitrogen. The residue was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (26 mg, 34%): LCMS (System A) RT=1.04 min, ES+ve m/z 523/524 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C(Cl)=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40][NH2:41])[CH3:37]>>[CH2:36]([N:38]([CH2:42][CH3:43])[CH2:39][CH2:40][NH:41][C:17]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:12][N:8]1[C:6](=[O:7])[CH:26]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:19])[CH3:37]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: CCON=C1C[C@@H](C(=O)NCCN(CC)CC)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 50% purity by LC/MS. MS(ESI+): m/z=465.4.
Reaction SMILES: C(S[C:4]1[S:8][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[O:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)=[CH:6][CH:5]=1)C.O1CC[CH2:39][CH2:38]1.[S:42]([OH:46])([O-])(=O)=[O:43].S(O)(OO)(=O)=O.[K+].[ClH:54]>O.ClCCl.CO>[ClH:54].[CH2:38]([S:42]([C:4]1[S:8][C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[O:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:35][CH:36]=2)=[CH:6][CH:5]=1)(=[O:46])=[O:43])[CH3:39]
Reactant: CCSc1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Reactant: C1CCOC1
Reactant: O=S(=O)([O-])O
Agent: Cl
Agent: O=S(=O)(O)OO
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add 1-(2-(4-(2-(5-(ethylthio)thiophen-2-yl)-6-methoxynaphthalen-1-yloxy)phenoxy)ethyl)piperidine (226 mg, 0.43 mmol), tetrahydrofuran (8.7 mL) and methanol (8.7 mL) to a round bottom flask under nitrogen. Cool the resulting solution to 0° C. and add a solution of potassium peroxymonosulfate sulfate (535 mg. 0.87 mmol) in water (4.5 mL). Stir the resulting mixture at 0° C. for 30 min. Allow the mixture to warm to room temperature and stir for 1 hour. Load the mixture onto an SCX acidic ion exchange column. Flush column with a 1:1 mixture of methanol and dichloromethane then elute with a 1:1 mixture of 2M ammonia in methanol and dichloromethane. Concentrate the ammonia containing eluent in vacuo to give an off white foam. Dissolve the foam in dichloromethane and treat with HCl (1M in ether; 900 uL). Concentrate the resulting mixture in vacuo to obtain the title compound (142 mg, 0.24 mmol): mass spectrum (m/z): 552 (M+1-HCl).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([C:17](=[O:19])[CH3:18])[CH3:1])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CNc1ccc(O)cc1
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(N(C)C(C)=O)cc1

Procedure:
To a flask was added 20.0 g. of 4-(N-methylamino)phenol, 20 ml. of acetic anhydride, 60 ml. of acetic acid and 10 g. of sodium acetate. The solution was warmed on a steam bath for one hour and water added to clarify the solution. The mixture was allowed to cool, more water added and the resulting solution poured onto solid sodium bicarbonate in an open vessel. The aqueous material was extracted five times with 200 ml. portions of ethyl ether, the ether extracts combined, washed with brine, then dried and concentrated to obtain the crude 4-(N-acetyl-N-methylamino)phenyl acetate which was recrystallized from a mixture of ethyl acetate, hexane and ethanol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:18][P-](F)(F)(F)(F)F.F[C:26]1[CH:27]=[CH:28][C:29]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:30]([CH:34]=1)[C:31](O)=[O:32].C(N(CC)CC)C.O.[Cl-].[Na+].O.CN([CH:54]=[O:55])C>>[F:18][C:28]1[C:29]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:30]([CH:34]=[CH:26][CH:27]=1)[C:31]([O:55][CH3:54])=[O:32]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(F)cc1C(=O)O
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc(F)c1NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 58 %

Procedure:
HATU (105.8 mg, 0.278 mmol) was added to a solution of 5-fluoro-2-(methylsulfonamido)benzoic acid (57.1 mg, 0.246 mmol) in 3 mL of anhydrous DMF at room temperature. After 15 min of stirring, intermediate 6 (44.8 mg, 0.182 mmol) was added followed immediately by triethylamine (0.040 mL, 0.288 mmol). Reaction mixture stirred at room temperature for 24 hours under argon. Mixture was then poured into a mixture of 40 mL of 1:1 water/brine and extracted three times with 40 mL of ethyl acetate. The combined organic layers were washed with 50 mL of 1:1 water/brine, dried (MgSO4), filtered, and concentrated under reduced pressure leaving a residue. Product was purified by silica gel column chromatography (0-10% Methanol in Dichloromethane) and then prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) to yield compound 11 (61 mg, 58%) as a white solid, trifluoroacetate salt, after lyophilization.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[C:20]([F:36])([F:35])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccccc1)c1ccccc1C(F)(F)F
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: FC(F)(F)c1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1

Procedure:
This material was prepared from 1-benzhydrol-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)benzhydrol (131) (15 mmol) using the procedure described for compound (3) (1.81 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]([CH2:29][CH:30]([C:32]1[C:36]([CH3:37])=[CH:35][S:34][C:33]=1[CH3:38])[OH:31])[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:13]=1[C:14]([F:17])([F:16])[F:15])=[O:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:42][C:40]1[CH:39]=[C:4]([CH:3]=[C:2]([F:1])[CH:41]=1)[CH2:5][N:6]([CH2:29][C:30]([C:32]1[C:36]([CH3:37])=[CH:35][S:34][C:33]=1[CH3:38])=[O:31])[C:7]([C:9]1[CH:10]=[N:11][N:12]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23]2)[C:13]=1[C:14]([F:15])([F:17])[F:16])=[O:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3cc(F)cc(F)c3)CC(O)c3c(C)csc3C)c2C(F)(F)F)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(C)csc3C)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 3-2 (290 mg, 0.47 mmol) in DCM (8 mL) was added Dess-Martin periodinane (401 mg, 0.94 mmol) at 0° C. and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous Na2S2O3 and NaHCO3, and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 3-3 (220 mg, 78%) as a colorless gum.
Reaction SMILES: [C:1]1([C:7]2([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Reaction time: 4 h
Yield: 54.5 %

Procedure:
To a solution of 3.89 g of 4-phenyl-4-(4-trifluoromethylphenoxy)piperidine in 25 ml of benzene was added a solution of 0.68 g of methyl isocyanate in 25 ml of benzene. The reaction mixture was stirred for four hours at room temperaure. Evaporation of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane). Recrystallization from 30% hexane/isopropyl ether yielded 2.46 g (54.19%) 1-(N-methylamino)carbonyl-4-phenyl-4-(4-trifluoromethylphenoxy)piperidine, m.p. 118°-120° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:23]3[C:24]([F:44])=[C:25]([N:29]([CH2:41][O:42][CH3:43])[S:30]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=3)=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl>[C:45]([N:20]1[CH2:19][CH2:18][CH:17]([N:15]2[CH:16]=[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)[C:13]([C:23]3[C:24]([F:44])=[C:25]([N:29]([CH2:41][O:42][CH3:43])[S:30]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=4[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=3)=[N:14]2)[CH2:22][CH2:21]1)(=[O:47])[CH3:46]
Reactant: COCN(c1cccc(-c2nn(C3CCNCC3)cc2-c2ccnc(NC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COCN(c1cccc(-c2nn(C3CCN(C(C)=O)CC3)cc2-c2ccnc(NC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of N-{3-[4-(2-tert-Butylamino-pyridin-4-yl)-1-piperidin-4-yl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (100 mg, 0.159 mmol) (prepared as described in example 8) in DCM (1.5 mL) triethylamine (0.024 mL, 0.175 mmol, 1.1 eq) was added, followed by acetylchloride (0.011 mL, 0.159 mmol, 1 eq) and the solution was stirred at r.t. for 1 h. The reaction mixture was then diluted with DCM and washed with water. The aqueous phase was back extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH/NH3 7N in MeOH 94.5:1) affording 93 mg (87%) of N-{3-[1-(1-Acetyl-piperidin-4-yl)-4-(2-tert-butylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide, HPLC (254 nm): Rt: 6.59 min; 1H NMR (DMSO-d6) Shift: 8.18 (s, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.58-7.66 (m, 1H), 7.45-7.58 (m, 3H), 7.23-7.35 (m, 2H), 6.26 (s, 1H), 6.15 (dd, J=1.1, 5.4 Hz, 1H), 5.76 (br. s., 1H), 5.01 (s, 2H), 4.43-4.56 (m, 2H), 3.89-3.97 (m, 1H), 3.30 (s, 3H), 3.17-3.25 (m, 1H), 2.69-2.78 (m, 1H), 2.02-2.16 (m, 2H), 2.05 (s, 3H), 1.94 (qd, J=4.6, 12.1 Hz, 1H), 1.79 (qd, J=4.5, 12.1 Hz, 1H), 1.31 (s, 9H); HRMS (ESI) calcd for C33H38F3N6O4S [M+H]+ 671.2622. found 671.2623.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=C[C:39]([O:43]C)=CC=3)CC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][C:16]([O:43][CH3:39])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCc3cc(OC)ccc32)n1
Product: CCc1nc(NC2CCc3cc(OC)ccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.29, 1.89, 2.56, 2.70, 2.83, 2.87, 3.00, 3.83, 4.49, 5.61, 6.81, 6.85, 7.23; HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1008.