Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(OCCN(CC)CC)C=CC=1C(=O)C(=C)CC.[Cl:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:26]=[CH:25][C:24]=1[C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>>[Cl:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]([CH3:36])[CH2:32][N:33]([CH3:34])[CH3:35])[CH:26]=[CH:25][C:24]=1[C:37](=[O:41])[C:38](=[CH2:2])[CH2:39][CH3:40]
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CCCC(=O)c1ccc(OCC(C)CN(C)C)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCC(C)CN(C)C)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 2-chloro-4-(2-diethylaminoethoxy)butyrophenone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(3-dimethylamino-2-methylpropoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[C:59]([C:64]([F:66])([F:67])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.7 %

Procedure:
To a solution of 50 mg (0.26 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 82 mg of TBTU (0.26 mmol) in 4 ml DMF, were added 0.22 ml (1.28 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.28 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:2) to give 81 mg off-white foam (55%). MS (ISP) 531.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][C:36](=[O:38])[CH3:37])[CH2:3][CH2:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCC3)s2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NC1(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 92.4 %

Procedure:
To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B-1, 75 mg, 0.185 mmol) and Et3N (25.8 μL, 0.185 mmol) in THF (1000 μL), acetyl chloride (13.15 μL, 0.185 mmol) was added. The mixture was stirred at room temperature for 70 minutes. Additional acetyl chloride (6 μL) was added to drive the reaction to completion. The mixture was stirred for 10 additional minutes, then diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated to afford N-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}acetamide (80.8 mg, 0.171 mmol, 92%). MS ESI: [M+H]+ m/z 480.0. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.93 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.28 (d, J=4.9 Hz, 1H), 7.14 (s, 1H), 3.32-2.60 (m, 2H), 2.43-2.41 (m, 2H), 2.31 (s, 3H), 1.99-1.95 (m, 2H), 1.88 (s, 3H). rhSYK activity=+++
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C@H:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1
Reactant: CCc1cccc(C2(NCC(O)C(N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: O=C1CCCC(=O)O1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCCC(=O)O)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol (0.500 g, 1.387 mmol) in chloroform (7 ml) was added TEA (0.58 ml, 4.161 mmol) with stirring under nitrogen for 30 min. To this solution was added glutaric anhydride (0.158 g, 1.387 mmol) and reaction was stirred overnight at 50° C. The reaction mixture was concentrated in vacuo, yielding the product. (ES+: 475.2)
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19]>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9])=[O:19]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1ccccc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(2-chloro-phenyl)-N-methoxy-N-methyl-acrylamide (22 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (17 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:22][CH:21]([O:23][Si](C(C)(C)C)(C)C)[CH2:20]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(Cl)c(N3CC(O)C3)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
Under nitrogen mix 7-chloro-6-[3-(tert-butyldimethyl-silanyloxy)-azetidin-1-yl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (594 mg, 1.29 mmol), 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol), glacial acetic acid (0.2 mL, 3.33 mmol), 4 Å molecular sieve (650 mg) in anhydrous THF (18 mL). Stir at RT for 3 days. After the first day add more 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol) and glacial acetic acid (0.2 mL, 3.33 mmol). After the second day add more 1 N tetrabutylammonium fluoride solution in THF (2.04 mL, 2.04 mmol) and glacial acetic acid (0.2 mL, 3.33 mmol). Stop the reaction on the third day. Dilute with EtOAc and wash with saturated aqueous sodium bicarbonate solution and 0.1 N NaOH. Extract the aqueous layer three times with EtOAc. Combine the EtOAc fractions, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 EtOAc:hexanes) to give the title compound (325 mg, 72%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)O1.CCN=C=NCCCN(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.Br[C:38]1[CH:39]=[C:40]2[C:46]([C:47]3[CH:48]=[C:49]4[C:53](=[CH:54][CH:55]=3)[NH:52][CH:51]=[CH:50]4)=[CH:45][N:44](S(C3C=CC(C)=CC=3)(=O)=O)[C:41]2=[N:42][CH:43]=1>CN(C1C=CN=CC=1)C.CC#N.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>[NH:52]1[C:53]2[C:49](=[CH:48][C:47]([C:46]3[C:40]4[C:41](=[N:42][CH:43]=[C:38]([C:9]5[CH:10]=[CH:11][C:12]([C:13]([N:34]6[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]6)=[O:15])=[CH:16][CH:17]=5)[CH:39]=4)[NH:44][CH:45]=3)=[CH:55][CH:54]=2)[CH:50]=[CH:51]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CN1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (100 mg, 0.403 mmol), EDCI (97 mg, 0.504 mmol) and DMAP (catalytic amount) were combined in CH3CN, stirred for 10 min and treated with N-methylpiperazine (54 μl, 0.484 mmol). The mixture was stirred overnight at room temperature. An aliquot of 650 μl was taken, combined with Intermediate B (50 mg, 0.107 mmol) and dichlorobis(triphenylphosphine)palladium (II) (10 mg, 0.013 mmol) and heated to 150° C. in a microwave reactor for 20 min. The mixture was partitioned between water and DCM, the organic phase dried, evaporated and purified by silica gel chromatography using 0-6% MeOH:DCM. 13 mg (28%) of the title compound were obtained. 1H NMR (DMSO-d6, 300 MHz): δ 11.88 (d, J=1.5 Hz, 1H), 11.08 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.47 (m, 4H), 7.34 (t, J=2.6 Hz, 1H), 6.47 (t, J=2.4 Hz, 1H), 3.58 (bs, 4H), 2.3 (bs, 4H), 2.18 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[NH2:9][CH2:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: [H][H]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCc1cncc(F)c1
Reaction time: 18 h

Procedure:
In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4 g). Place on a Parr Shaker Apparatus under 60 psi hydrogen for 1 h at ambient temperature. Filter the reaction mixture and bubble ammonia gas into filtrate for 10 min. Add Raney® nickel (5.2 g) and place on a Parr Shaker Apparatus under 500 psi hydrogen for 18 h at 60-70° C. Filter the reaction mixture and concentrate in vacuo. Dissolve in methanol and add 1N hydrogen chloride in ether until form a precipitate. Cool in an ice bath, filter off the precipitate, wash the solid several times with ether, and dry to give the title compound as the hydrochloride salt (12 g, 70%). MS (ES+) m/z: 127 (M+H)+. Dissolve the hydrochloride salt in water, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, dry the organic layer over Na2SO4, filter and concentrate to give the title compound.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([C@@:15]12[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]>C1COCC1>[CH2:13]([C@@:15]12[CH2:39][CH2:38][C@@:37]3([CH2:8][O:40]3)[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]
Reactant: C[S+](C)(C)=O
Reactant: CC[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC[C@@]12CC[C@@]3(CO3)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C

Procedure:
Sodium hydride (60 wt % in oil, 0.023 g, 0.967 mmol) was added carefully to a flask containing about 3 mL DMSO then heated to about 65° C. for about 30 min. The reaction was cooled to rt then diluted with 2 mL THF. The reaction was further cooled in an ice water bath and trimethylsulfoxonium iodide (0.213 g, 0.967 mmol) was added in one portion and stirred about 15 min. (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.182, 0.483 mmol) in 2 mL THF was introduced via syringe and allowed to warm to rt over about 18 hrs. THF was removed in vacuo and the residue was diluted with 15 mL water and extracted with EtOAc (15 mL×3). The combined organics were washed with sat. aq. NaCl. The organic layer was dried over MgSO4 filtered and concentrated to a crude viscous oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl>[CH3:19][S:16]([O:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tetrahydro-2H-pyran-3-ylmethanol (4.92 g) in dry dichloromethane (140 ml) at 0° C. and under nitrogen, was added anhydrous triethylamine (13.6 ml) in one go, followed by mesyl chloride (4.3 ml) dropwise over 5 minutes. The reaction was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (50 ml). The organic layer was separated, passed through a hydrophobic frit to dry and concentrated in vacuo to yield a red oil (8.8 g).
Reaction SMILES: [CH3:1][C:2]([OH:4])=[O:3].CC(O)=[O:7].C1C(N/C(/N)=N/C(/N)=N/CCCCCC/N=C(\N)/N=C(\N)/N[C:32]2[CH:37]=[CH:36][C:35](Cl)=[CH:34]C=2)=CC=C(Cl)C=1.[C:43]1(N)[C:48](F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH2:48]([O:3][C:2]([C:1]1[CH:34]=[CH:35][C:36]([OH:7])=[CH:37][CH:32]=1)=[O:4])[CH3:43]
Reactant: NC(=N\CCCCCC/N=C(N)/N=C(\N)Nc1ccc(Cl)cc1)/N=C(\N)Nc1ccc(Cl)cc1
Reactant: CC(=O)O
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CCOC(=O)c1ccc(O)cc1

Procedure:
Chlorhexidine Diacetate, Digluconate or Dihydrochloride
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][N:18]([CH:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Br:40])[CH:37]=3)[O:32][CH2:31]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[O:20])[CH2:10][C@@H:9]1[CH3:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[Br:40][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH:30]([N:18]([CH2:17][CH2:16][CH2:15][N:11]1[CH2:10][C@H:9]([CH3:41])[NH:8][CH2:13][C@H:12]1[CH3:14])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1)=[O:20])[CH2:39]2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Yield: 95.8 %

Procedure:
(2S,5R)-4-{3-[1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-ureido]-propyl}-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.053 g, 0.081 mmol) was treated with 20% TFA/CH2Cl2 (0.4 mL) at room temperature for 2 hours. The reaction mixture was diluted with toluene (4 mL) and concentrated in vacuo. Purification on reverse-phase HPLC gave 0.043 g (96%) of (2R,5S)-1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(2,5-dimethyi-pipe razin-1-yl)-propyl]-urea as a white solid. 1H NMR (300 MHz, CD3OD): □ 7.83 (dd, J=6.6, 2.4 Hz, 1H), 7.53 (m, 2H), 7.45 (dd, J=8.7, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 4.71 (m, 1H), 4.46 (m, 2H), 4.07 (m, 1H), 4.00-3.20 (m, 10H), 2.26 (m, 2H), 1.66 (d, J=6.2 Hz, 3H), 1.63 (d, J=6.6 Hz, 3H). MS-ESI: 553.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=[CH:6][C:5]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[CH:23][C:22]=1[N+:37]([O-])=O)([O-])=O.[H][H]>C(O)C.[Pt]=O>[NH2:37][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:35])([F:36])[F:34])[CH:25]=[CH:26][C:21]=1[O:20][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:17])([F:18])[F:19])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2C(F)(F)F)ccc1Oc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)ccc1Oc1ccc(-c2ccccc2C(F)(F)F)cc1N
Yield: 49.3 %

Procedure:
2-Nitro-α,α,α-trifluoro-p-tolylphenyl ether (57.0 g., 0.209 mole) is dissolved in ethanol (200 ml.) and shaken in an atmosphere of hydrogen in a Parr apparatus in the presence of platinum oxide (100 mg.) until uptake is complete. The catalyst is removed by filtration and the solvent stripped off to give 2-amino-α,α,α-trifluoro-p- tolyl phenylether (50.3 g. 99%) which is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][CH2:7][OH:8])([O-:3])=[O:2].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1CCO
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2[N+](=O)[O-])cc1
Yield: 92 %

Procedure:
2-Nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 2-nitrophenethyl alcohol (15 g, 89.7 mmol) and tosyl chloride (20.52 g, 110 mmol). The residue was triturated with hexanes and 26.44 g of off white crystals were collected. Yield 92%; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=9.7 Hz, 1H), 7.91 (d, J=9.7 Hz, 2H), 7.64 (t, 1H), 7.39 (m, 2H), 7.24 (s, 2H), 4.32 (t, J=6 Hz, 2H), 3.24 (t, J=6 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19]([OH:20])=[N:18][C:11]2[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=2[CH:9]=1.O[O:22][S:23]([O-:25])=O.[K+].O1CCC[CH2:28]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:19]([OH:20])=[N:18][C:11]2[N:12]=[C:13]([S:23]([CH3:28])(=[O:25])=[O:22])[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: C1CCOC1
Reactant: CSc1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 6-(2-chlorophenyl)-2-methylthio-pyrido[2,3-d]pyrimidin-7-ol (25.2 g, 82.9 mmol) in 700 mL of tetrahydrofuran was added a slurry of Oxone™ (105 g, 171 mmol) in 200 mL of water. The reaction mixture was stirred for 5 hours, filtered, then concentrated in vacuo. The resulting slurry was filtered and the collected solid was washed with water and dried to give 23.2 g (83%) of 6-(2-chlorophenyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-ol (Sulfone 2) as a light-yellow solid. (mass spec. M+H+=336, mp=215.1-221.1° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([C:19](OC(C)(C)C)=[O:20])[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)C(Cl)=O.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([C:19](=[O:20])[C:38]5[CH:37]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:39]=5)[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of the product from Example 205C (40 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes, and then it was concentrated in vacuo. To the residue was added CH2Cl2 (1 mL), 3-(trifluoromethyl)benzoyl chloride (0.020 mL, 0.130 mmol), and triethylamine (0.045 mL, 0.324 mmol), and the resulting mixture was stirred at ambient temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% methanol in dichloromethane to give the title compound (36 mg, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 0.88-1.02 (m, 4 H) 1.37-3.27 (m, 6 H) 3.55-3.93 (m, 2 H) 4.07-4.31 (m, 1 H) 4.64-5.14 (m, 1 H) 5.49-5.68 (m, 1 H) 7.56-7.67 (m, 2 H) 7.68-7.80 (m, 2 H) 7.94 (s, 1 H) 8.08-8.20 (m, 1 H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: ClCCCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC#CCCCCl)ccc(C(C)=O)c1O
Yield: 87.2 %

Procedure:
A mixture of 3.10 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 3.13 g of 1-bromo-6-chloro-2-hexyne and 3.30 g of anhydrous potassium carbonate in 35 ml of anhydrous acetone was stirred at reflux for 2.5 hours. The solvent was removed in vacuo, water was added to the residue and the pH was adjusted to 4.0. The product was extracted with ether and the dried (over magnesium sulfate) extract was chromatographed on 250 g of silica gel. Elution with 25% ethyl acetate-hexane gave 4.30 g (88% yield) of 6-(4-acetyl- 3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne, the titled compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
(Step 1) tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.5 g, 12 mmol) and triethylamine (2.1 mL, 15 mmol) were dissolved in dichloromethane (30 mL). To the solution was added a solution of methanesulfonyl chloride (1.2 mL, 15 mmol) in dichloromethane (10 mL), followed by stirring for 4 hours, while the temperature was raised to room temperature. To the reaction mixture was added water (50 mL), and the mixture was stirred for 30 minutes, followed by liquid separation. The organic layer was washed successively with 0.50 mol/L hydrochloric acid (40 mL×2) and a saturated aqueous solution of sodium hydrogencarbonate (10 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting residue was added a mixed solvent of ethyl acetate and hexane (15 mL, ethyl acetate/hexane=1/2), and the precipitated solid was filtered to obtain tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (3.1 g, 90%).