Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2>C(Cl)Cl>[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][N:44]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and isobutyryl chloride (44 mg, 0.41 mmol), in methylene chloride (0.5 ml) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material bad gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 2% methanol/methylene chloride gave 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline (90 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[C:25]([F:28])([F:27])[F:26])[N:12]=1)=[O:9].B(Br)(Br)Br>ClCCl>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH:14]=[CH:15][C:11]([NH:10][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[CH3:1])=[O:9])=[N:12]2)=[C:18]([C:25]([F:27])([F:28])[F:26])[CH:19]=1
Reactant: COc1ccc(Cn2ccc(NC(=O)c3ccncc3C)n2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cnccc1C(=O)Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1
Reaction time: 48 h

Procedure:
To a solution of 3-methyl-N-(1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-4-pyridinecarboxamide (for a preparation see Example 175)(50 mg, 0.128 mmol) in dichloromethane (1 mL) was added slowly 1.0 M boron tribromide in DCM (0.26 mL, 0.260 mmol). The resulting colourless solution was stirred under nitrogen for 2 days. The reaction mixture ran dry, so further amounts of dichloromethane (1 ml) and 1.0 M boron tribromide in DCM (0.26 mL, 0.260 mmol) were added. The resulting white suspension was stirred at ambient temperature under nitrogen overnight. A further amount of 1.0 M boron tribromide in DCM (0.26 ml, 0.26 mmol) was added and stirred for a further 4 h. The solvent was removed in vacuo and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on an Xbridge column using Acetonitrile-Water with an ammonium carbonate modifier (Method E). The solvent was evaporated in vacuo to give the title compound as a white solid (11 mg); LCMS (System 8) MH+=376, tRET=2.13 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.ClC1C2C(=CC(Cl)=C(Cl)C=2)OC(=O)C=1.O1C2C=CC(N3CCC(N)CC3)=CC=2OC1>>[NH:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[O:5][C:4](=[O:16])[CH:3]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=c1cc(Cl)c2cc(C(F)(F)F)ccc2o1
Agent: NC1CCN(c2ccc3c(c2)OCO3)CC1
Agent: O=c1cc(Cl)c2cc(Cl)c(Cl)cc2o1
Product: O=c1cc(NC2CCNCC2)c2cc(C(F)(F)F)ccc2o1

Procedure:
4-(Piperdin-4-ylamino)-6-trifluoromethyl-chromen-2-one was prepared according to the procedure described in Example 76, except that crude 4-chloro-6-trifluoromethyl-chromen-2-one (423 mg, 1.7 mmol) and 4-amino-1-N-Boc-piperidine (359 mg, 1.79 mmol) were used in place of 4,6,7-trichlorochromen-2-one and 1-benzo[1,3]dioxol-5-yl-piperdin-4-ylamine, to give a white solid (521 mg). Removal of the BOC protecting group provided the free base as a white solid (272 mg, 69%). MS (APCI) m/z 313 [M+H]+, 311 [M−H]+; 1H NMR (300 MHz, DMSO-D6) δ ppm 1.81 (m, 2H) 2.10 (m, 2H) 3.03 (m, J=2.37 Hz, 2H) 3.39 (m, 2H) 3.84 (m, 1H) 5.50 (s, 1H) 7.52 (d, J=8.48 Hz, 1H) 7.68 (d, J=7.80 Hz, 1H) 7.95 (d, J=8.82 Hz, 1H) 8.66 (s, 1H) 8.72 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[C:10]([N:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:11]([F:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)C1C=CC=CC=1.[CH3:29][C:30]([CH3:45])([CH2:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1)[CH2:31][OH:32]>>[F:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([CH2:35][CH2:34][CH2:33][C:30]([CH3:45])([CH3:29])[CH2:31][OH:32])[CH:13]=2)[CH:18]=[C:9]([OH:8])[C:10]=1[N:21]1[S:25](=[O:26])(=[O:27])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: CC(C)(CO)C/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CN(c2c(OCc3ccccc3)cc3ccc(Br)cc3c2F)S(=O)(=O)N1
Product: CC(C)(CO)CCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2c1

Procedure:
The title compound is prepared analogously to Example 9, Steps A and B, starting from 5-(3-benzyloxy-7-bromo-1-fluoronaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and (E)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pent-4-en-1-ol, Retention time=1.16 min (Method A); MS (M−H)−=409.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([O-])=[O:20].[K+].CC(OC(C)=O)=O>CC#N>[O:17]=[C:10]1[NH:9][C:8]([C:4]2[CH:3]=[C:2]([O:1][C:19](=[O:20])[CH3:18])[CH:7]=[CH:6][CH:5]=2)=[N:13][C:12]2[CH:14]=[CH:15][S:16][C:11]1=2
Reactant: CC(=O)[O-]
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1

Procedure:
A mixture of 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 26, (10.95 g, 44.8 mmol), KOAc (6.6 g, 67.2 mmol) and Ac2O (16.5 mL, 0.175 mol) in MeCN (150 mL) were heated at reflux temperature for 24 h. The cooled reaction mixture was poured onto water (500 mL) and the resulting precipitate was collected by filtration. This was then washed with water and dried to furnish acetic acid 3-(4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-phenyl ester, 27, as a grey solid (10.87 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9](Cl)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: Nc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-amino-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 206°-208° C.) and piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:13]([CH3:23])[N:12]=[C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)c(C)c1
Yield: 82.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(3,4-dimethylphenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.083 g; 0.214 mmol), sodium hydroxide 10N (0.214 mL; 2.14 mmol) in methanol (2 mL) to afford 0.066 g (81%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][S:34]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][S:34]([CH3:33])(=[O:35])=[O:36])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 3) to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. LR-MS: 635.1 [(M+H)+].
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (example 162) (0.2 g, 0.34 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) to yield the title compound as an off-white solid (0.12 g, 67%). MS (ISN) 529.3 [(M−H)−]; mp 262° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CC#N>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(c2cccc(C=O)n2)CC1
Temperature: 110 °C
Yield: 31.8 %

Procedure:
A suspension of 6-bromopicolinaldehyde (1.50 g, 8.10 mmol), 1-methylpiperazine (2, 4.04 g, 40.0 mmol), potassium carbonate (4.46 g, 32.0 mmol) and anhydrous CH3CN (10 mL) was placed in a sealed vessel and the mixture was heated at 110° C. for 17 h. The mixture was diluted with water (50 mL) and brought to pH 7 using 2 N aq. HCl (15 mL). The resulting solution was extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine (200 mL). The solution was dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.528 g, 32%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.84 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.27 (d, J=7.0 Hz, 1H), 6.85 (d, J=7.0 Hz, 1H), 3.67-3.65 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)[CH:7]=1.N([O-])=[O:30].[Na+].NC(N)=O>O.ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([OH:30])[CH:3]=[CH:4][C:5]=2[C:25]([F:28])([F:27])[F:26])[N:10]=1)=[O:24]
Reactant: Nc1ccc(C(F)(F)F)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2cc(O)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 5 °C

Procedure:
To a suspension of N-(1-{[5-amino-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Intermediate 41) (1.0 g, 2.52 mmol) in water (15 ml) in an ice-water bath was added a solution of sodium nitrite (0.346 g, 5.01 mmol, Aldrich) in water (3 ml). The solution was maintained at 0-10° C. for 20 min. To the solution was added urea (0.94 g, 15.65 mmol, Aldrich) and then copper (II) sulphate (0.139 g, 0.868 mmol, Fluka). The mixture was heated to 90° C. for 30 min. The mixture was partitioned between water (150 ml) and ethyl acetate (130 ml). The phases were separated and the aqueous phase washed with ethyl acetate (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica 100 g using a 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an orange solid (0.462 g); LCMS: (System 4) MH+=398, tRET=2.36 min.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11]Cl.Cl.[CH2:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11][O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:21]
Reactant: CC1(C)[C@H]2CC[C@@H](CCCl)[C@@H]1C2
Reactant: OCCCCCO
Agent: Cl
Agent: [Na]
Product: CC1(C)[C@H]2CC[C@@H](CCOCCCCCO)[C@@H]1C2
Temperature: 130 °C

Procedure:
Over the course of 12 hours, 12.2 g of elemental sodium were dissolved in portions in 357 ml of 1,5-pentanediol at a temperature of 90° C. 80 g of 2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-y l)ethyl chloride were then added dropwise to this solution, and the reaction mixture was heated at 130° C. for 15 hours. The reaction mixture was worked up by cooling to room temperature, adding 300 ml of a 5% strength aqueous hydrochloric acid solution, and extracting the mixture with ether. After concentrating the ether extract, 99.6 g of crude 5-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl )ethoxy]pentanol were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)[CH2:14][CH2:13]2)[CH3:10])=[O:8])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:10])[CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]#[C:19][CH2:20][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C1CCNCC1
Solvent: CO
Product: CN(C[C@H]1CC[C@H](C#CCN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 222 mg (corresponds to 0.40 mmol) of crude trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester in 4 ml of methanol was cooled to 0° C., treated with 0.34 ml (4 mmol) of piperidine and stirred over night at room temperature. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/ether (3×). The organic phase was dried with sodium sulfate, filtered and evaporated. Purification by flash column chromatography on silica gel (methylenechloride/methanol 99:1 to 98:2) gave 92 mg (57%) of pure trans-methyl-[4-(3-piperidin-1-yl-prop-1-ynyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 403 (MH+, 1Cl). The following compounds were prepared from the corresponding mesylates and secondary amines:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=CC=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]([N+:35]([O-:37])=[O:36])=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:35]([C:28]1[CH:27]=[CH:26][C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=2)=[CH:30][C:29]=1[C:31]([F:34])([F:33])[F:32])([O-:37])=[O:36]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(C(F)(F)F)C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 95.9 %

Procedure:
16.0 g (47.6 mmol) of 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 26.9 g (119 mmol) of 5-chloro-2-nitrobenzotrifluoride and 20.2 g (190 mmol) of sodium carbonate were reacted at 150° C. for 4 hours in 100 ml of dimethylformamide. After the reaction, the product was injected into 250 ml of iced water and extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. After filtration, the solvent was distilled off to recover a crude product, which was then purified by silica gel column chromatography (eluent: toluene/hexane=1/1) and then treated by activated carbon to obtain 32.6 g (yield: 95.9%) of 2,2-bis[(4-(4-nitro-3-trifluoromethylphenoxy)phenyl]hexafluoropropane.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]#[N:28]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[N:22]([CH3:21])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: Cn1cccc1C#N
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 1. MS (ES) m/z 265.1. HRMS: calcd for C17H16N2O+H+, 265.13354; found (ESI, [M+H]+), 265.1332.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([CH:10]([CH3:12])[CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:12])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(Nc2ncc(F)c(Nc3cccc(C(C)C)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline were reacted to give N2,N4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 29.58 min.; Purity: 98%; MS (m/e): 365 (MH+); 1H NMR (DMSO-d6): δ 10.5 (1H, s), 10.34 (1H, s), 8.41 (1H, d, J=5.1 Hz), 7.62 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=8.1 Hz), 7.37 (2H, m), 7.29 (1H, t, J=8.1 Hz), 7.19 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz), 2.88 (2H, m), 1.25 (6H, d, J=7.2 Hz), 1.201 (6H, d, J=7.2 Hz).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (858 mg, 5.15 mmol), HOBt (704 mg, 5.15 mmol, 1.0 eq.) and benzylamine (0.745 ml, 6.70 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.19 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:12]1([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si](Cl)(C)C>ClCCCl>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([NH:21][C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:21][C:19](=[O:20])[CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CN(C)c1ccc(C(NC(=O)Cc2ccccc2)NC(=O)Cc2ccccc2)cc1
Temperature: 70 °C
Yield: 34.9 %

Procedure:
To a suspension of 4-(dimethylamino)benzaldehyde (149 mg, 1 mmol) and 2-phenylacetamide (270 mg, 2 mmol) in 2 mL anhydrous DCE, TMSCl (216 mg, 2 mmol) was added. The mixture was heated at 70° C. for 12 h, then cooled to room temperature and the crude product precipitated from the solution. The crude product was recrystallized with methanol and hexane to give the final product (140 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=8.0 Hz, 2H), 7.59 (s, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.21-7.32 (m, 10H), 6.54 (t, J=8.0 Hz, 1H), 3.52 (dd, J=14.0, 15.6 Hz, 4H), 3.06 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([CH3:13])(O)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[FH:37].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([F:37])([CH3:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 42 °C
Reaction time: 15 h

Procedure:
To a solution of 5.5 g (13.5 mmole) of (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl) azetidin-3-yl]-2-methylpropan-2-ol in 25 mL of CH2Cl2 was added 15 mL of hydrogen fluoride-pyridine and the two-phase mixture was stirred for 15 h at 42° C. Then the reaction mixture was poured to 100 mL of 5N NaOH, 20 mL of aq NaHCO3, 150 mL of CH2Cl2 and 100 mL ice. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×1500 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.25 ( t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.30 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 10H); Mass Spectrum: m/e=410 (M+1)