Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:31][S:32](O)(=[O:34])=[O:33].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 13; 0.10 g, 0.24 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.24 mmol), DIEA (0.062 g, 0.48 mmol), DMAP (0.032 g, 0.26 mmol), and THF (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 63%). 1H NMR (400 MHz, CD3OD) δ 7.48-7.45 (m, 2H), 7.20 (d, J=10.9 Hz, 1H), 7.05-7.01 (m, 2H), 5.30 (s, 1H), 5.04-5.01 (m, 1H), 4.56-4.53 (m, 1H), 4.20 (d, J=14.4 Hz, 1H), 4.12 (d, J=14.4 Hz, 1H), 3.86-3.73 (m, 2H), 3.01 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). MS: Calcd.: 496. Found: [M+H]+ 497.
Reaction SMILES: [CH3:1][SiH:2]1[O:9][SiH:8]([CH3:10])[O:7][SiH:6]([CH3:11])[O:5][SiH:4]([CH3:12])[O:3]1.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15].C1C=CC=CC=1>[Zn](OC(C)=O)OC(C)=O.O>[C:13]([O:17][CH2:18][CH2:19][O:20][Si:8]1([CH3:10])[O:9][SiH:2]([CH3:1])[O:3][SiH:4]([CH3:12])[O:5][SiH:6]([CH3:11])[O:7]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)OCCO
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Agent: CC(=O)O[Zn]OC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: C=CC(=O)OCCO[Si]1(C)O[SiH](C)O[SiH](C)O[SiH](C)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution containing 1M of 2,4,6,8-tetramethylcyclotetrasiloxane and 0.01 g of (CH3CO2)2Zn was slowly added 1M of 2-hydroxyethyl acrylate. The resulting mixture was stirred for 12 hours at a room temperature. Thereafter, 200 mL of benzene and 200 mL of cold water were added. The organic layer was separated, washed with 200 mL of cold water, dried over MgSO4, filtered and concentrated by distillation to provide the title compound of Formula 1A (yield: 97%).
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1.[Cu]I>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5])[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 24.5 %

Procedure:
Into a solution of 2-bromo-4-chloronicotinaldehyde 103a (446 mg, 2.05 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one 101h (300 mg, 1.36 mmol) in dioxane (50 mL) was added KAcO (267 mg, 2.72 mmol), CuI(259 mg, 1.36 mmol), and 4,7-dimethoxy-1,10-phenanthroline (327 mg, 1.36 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 90° C. for 10 h. It was allowed to cool down to room temperature and H2O (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with 10:1 PE/EA to afford 103b (120 mg, 25%). LCMS: [M+H]+ 360. 1H NMR (500 MHz, CDCl3) δ 10.36 (s, 1H), 8.69 (d, J=5.5, 1H), 8.28 (d, J=2.0, 1H), 7.28-7.56 (m, 3H), 1.49 (s, 9H)
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][NH3+:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C.O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)C[NH3+]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of 2-(tert-butoxy)-2-oxoethanaminium chloride (3.00 g, 17.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (20 mL) was stirred at room temperature for 2 min. To the reaction mixture was added 4-(bromomethyl)benzonitrile (3.19 g, 16.3 mmol) and stirring continued for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (3×20 mL). The combined organic extract was dried over MgSO4 then concentrated. Purification of the crude product by a silica gel column (DCM/MeOH) gave 2.77 g (68%) of tert-butyl 2-((4-cyanobenzyl)amino)acetate INT-31 as a yellow oil. LCMS-ESI (m/z) calculated for C14H18N2O2: 246; found 247 [M+H]+, tR=0.92 min (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24]OS(C)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:24][CH2:23][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:16][C:12]=1[CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1F

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3-fluoro-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-ethoxy-methyl)-triphenyl-phosphonium chloride (prepared in analogy to the procedure described for the synthesis of (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride in example 114 a]) then gave 2(Z,E)-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:3])=O.N1C2C(=CC=CC=2)C(=O)NC1=O.BrCCC1C=C(C=CC=1)C(OC)=O.[N:49]1([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[N:56]1[CH:57]=[CH:58][CH:59]=[N:60][C:55]=1[N:49]1[CH2:54][CH2:53][N:52]([C:1]([C:4]2[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][C:10]2=[O:20])=[O:3])[CH2:51][CH2:50]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(CCn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: COC(=O)c1cccc(CCBr)c1
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: O=C(c1cccc(CCn2c(=O)[nH]c(=O)c3ccccc32)c1)N1CCN(c2ncccn2)CC1

Procedure:
The compound was prepared from 1-(3-carboxyphenethyl)quinazoline-2,4(1H,3H)-dione (prepared from quinazoline-2,4(1H,3H)-dione and methyl 3-(2-bromoethyl)benzoate using a procedure similar to those used for Examples 1 and 2) and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.54 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.78 (dd, J=7.8 and 1.5 Hz, 1H), 7.73 (t, J=6.9 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.35-7.22 (m, 5H), 6.66 (t, J=4.7 Hz, 1H), 4.28 (t, J=7.5 Hz, 2H), 3.80-3.20 (m, 8H), 2.95 (t, J=7.4 Hz, 1H). MS: m/z 457.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:5][CH:4]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.C(O)C>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[S:13][C:12](=[O:14])[NH:11][N:10]=3)=[CH:7][CH:8]=2)[CH:16]=[CH:17]1
Reactant: Nc1ccc(-c2n[nH]c(=O)s2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)s3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-thiadiazol-2(3H)-one hydrochloride (1.25 g), 4H-pyran-4-one (0.58 g), ethanol (10 ml) and water (50 ml) was stirred under reflux under nitrogen for 31/2 hours. The cooled reaction mixture was filtered and the collected orange solid was washed with aqueous potassium hydrogen carbonate and water and was dried. The crude product (1.35 g) was treated with boiling dimethylformamide (200 ml) and the resultant suspension was cooled and filtered. The collected solid was washed with ethanol and ether, dried and suspended in water (100 ml). Sufficient aqueous sodium hydroxide (2N) was added to the suspension to form a solution which was filtered. The filtrate was acidified to pH 6 with hydrochloric acid which caused the precipitation of the title compound as a yellow solid, 0.96 g, m.p. 343°-4° C. (decomp).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[CH:29]>>[CH3:34][S:31]([NH:30][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:29]=1)(=[O:33])=[O:32]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCCCCNS(C)(=O)=O
Product: CS(=O)(=O)NCCCCc1cn(C2CCc3c(CC(=O)O)c4ccccc4n3C2)nn1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and N-hex-5-yn-1-ylmethanesulfonamide. MS (+ESI) m/z: 446.2.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[NH2:35])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([NH:35][C:3](=[O:4])[O:2][CH3:1])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: COC(=O)Cl
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Methylchoroformate (16 μL, 0.21 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (64 mg, 0.11 μmol) and triethylamine (31 μL, 0.22 mmol) in dichloromethane (5 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford methyl {2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}carbamate which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CC1C2[O:20]C=CC=2C=CC=1>>[CH3:11][C:10]1[C:4]2[O:3][C:2]([CH:1]=[O:20])=[CH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc2ccoc12
Reactant: Cc1cc2cccc(C)c2o1
Product: Cc1cccc2cc(C=O)oc12

Procedure:
2,7-Dimethyl-benzofuran. 7-Methyl-benzofuran (cf. compound (2) g.) is subjected to a WILSMEYER reaction to form 7-methyl-benzofuran-2-aldehyde which is converted into 2,7-dimethyl-benzofuran by a WOLFF-KISHNER reaction by the method described in Bull.Soc.Chim.France 29, 1875 (1952). The product thus obtained has the following peaks in its MS: 146 (100%), 145 (92%) and 131 (32%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1cccc(I)c1
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: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccccc3c2)c1
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 243 g (1.41 mol) of 2-naphthaleneboronic acid, 400 g (1.41 mol) of 3-bromoiodobenzene, 3.27 g (28.2 mmol) of tetrakis(triphenylphosphine)palladium(0), 6.4 L of toluene and 3.2 L of aqueous solution of 2M sodium carbonate were added together, and stirred while being refluxed for 24 hours. After the reaction was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was washed by water and dried with magnesium sulfate, the toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 303 g of 2-(3-bromophenyl)naphthalene was obtained at an yield of 76%.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.[NH2:18][C@H:19]([CH3:22])[CH2:20][OH:21]>C(O)(C)C>[NH2:8][C:7]1[C:2]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:3][C:4]([CH3:10])=[N:5][C:6]=1[Cl:9]
Reactant: C[C@@H](N)CO
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1nc(Cl)c(N)c(N[C@H](C)CO)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Charge 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (307 g, 1.72 moles) into a 10 L flange flask mounted on an isomantle equipped with an overhead stirrer, reflux coil condenser, thermometer, and addition funnel. Then add isopropyl alcohol (3.45 L) to the flask and stir to give a clear pale yellow solution. Add triethylamine (456.7 mL, 3.28 mol) to the flask in one portion while stirring and warm to 50° C. Slowly add (R)-(−)-2-amino-1-propanol (194.30 g, 202.10 mL, 2.59 mol) from the addition funnel over 30 min. After the final addition heat the reaction mixture at reflux for 36 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (64.77 g, 67.37 mL, 862.26 mmol, 0.5 eq) and triethylamine (174.51 g, 240.37 mL, 1.72 moles, 1.0 eq) to the reaction mixture and reflux for 18 h. Allow the reaction mixture to cool. Add additional (R)-(−)-2-amino-1-propanol (32.38 g, 33.68 mL, 431.13 mmol, 0.25 eq) and triethylamine (87.25 g, 120.18 mL, 862.26 mmol, 0.5 eq) to the reaction mixture and heat to reflux for 6 h. Allow to cool while stirring at ambient temperature for 48 h.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][OH:15])[N:11]=[C:4]2[N:3]=1.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][O:15][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])=[CH:21][CH:22]=3)[N:11]=[C:4]2[N:3]=1
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: Cc1cc(C)n2nc(SCCO)nc2n1
Product: Cc1cc(C)n2nc(SCCOc3ccc(CCN(C)C)cc3)nc2n1
Yield: 48 %

Procedure:
The title compound was prepared according to the experimentals described for Example 31 above from of 2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl sulfanyl)ethan-1-ol and N,N-dimethyltyramine in 48% yield; EM (calc.): 371.2; MS (ESI) m/e: 372.2 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH3:35])[CH:28]=[C:29]([O:33]C)[C:30]=1[O:31][CH3:32].CO>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:28]1[C:29]([OH:33])=[C:30]([O:31][CH3:32])[C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:35])=[O:17]
Reactant: CC(=O)OCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of 12-acetoxy-n-dodecanoyl chloride (8.5 g) in 1,2-dichloroethane (30 ml) is added aluminum chloride (8.2 g) and the mixture is stirred at room temperature for 2 hours. The mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (5.6 g) in 1,2-dichloromethane (20 ml) is added to the above mixture. The mixture is stirred at room temperature for 72 hours, and at 50° C.-60° C. for 30 minutes. Methanol (200 ml) is added to the reaction mixture and the mixture is stirred at 50° C. for 3 hours. The solvent is distilled off, and the residue is subjected to extraction with dichloromethane. The dichloromethane layer is washed with water and dried over magnesium sulfate. The solvent is distilled off to thereby leave crude crystals. The product is recrystallized from ether-hexane (1:1) to give 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (8.5 g) as colorless needles. Melting point 82° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCN2CCOCC2)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
A solution of 3-bromo-N-{5-[2-(4-fluoro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide (20 mg, 0.046 mmol) and morpholine (8 μL, 0.092 mmol,) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as a pale solid. Anal. RP-HPLC: tR=13.3 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>93%). 1H-NMR (CD3OD) δ: 2.66 (s, 3H, CH3), 3.23 (m, 2H, CH2), 3.33 (m, 2H, CH2), 3.41 (m, 4H, CH2), 3.87 (m, 2H, CH2), 4.13 (m, 2H, CH2), 7.04-7.09 (m, 3H, pyrimidinyl-H & Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 443.3 (C21H23FN6O2S requires 442.5).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH2:24][C@H:25]2[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]2)=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.[O:32]1CCOCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+]>O>[OH:32][C:2]1[C:22]([O:23][CH2:24][C@H:25]2[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26]2)=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4
Reactant: C1COCCO1
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)OC[C@H](COc2cc3c(cc2O)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
9-Bromo-3-chloro-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-1, 30 mg, 0.06 mmol) was dissolved in the mixture solvent of water.dioxane (1:1) (0.5 mL), added with tris(benzylidenacetone dipalladium)chloroform complex (3.1 mg, 0.05 eq.), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.5 mg, 0.1 eq.) and KOH (0.5 N aqueous solution 180 μL, 1.5 eq.), and stirred at 60° C. for 12 hr. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residues were purified by HPLC to obtain the title compound (white solid, 4.6 mg).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[CH3:25][C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:27])[F:28])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH2:2][O:26]1
Reactant: CC(=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Trimethylsulfoxonium iodide (2.5 g, 11.6 mmol) was gradually added to a suspension of sodium hydride (484 mg, 12.1 mmol) in dimethylsulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-{4-(4-trifluoromethylphenyl)piperazin-1-yl}propan-2-one (3.4 g, 11.9 mmol) in dimethylsulfoxide (20 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resultant filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 1-(2-methyl-2-oxiranylmethyl)-4-(4-trifluoromethylphenyl)piperazine (3.2 g, yield 98%)as a light yellow powder.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)CCCC.[S:13]([O:20]S(C(F)(F)F)(=O)=O)([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14]>>[CH2:2]([O:20][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: CCCCCO
Product: CCCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a nitrogen flushed round bottom flask equipped with a stir bar was added pyridine (0.81 mL, 10.0 mmol) and n-pentanol (1.09 mL, 10.0 mmol). The reaction was cooled in an ice bath and triflic anhydride (1.69 mL, 10.0 mmol) was added dropwise. The ice bath was allowed to melt over two hours at which time the entire reaction mixture was filtered over a column of silica gel eluting with dichloromethane. The filtrate was carefully evaporated in vacuo then carried on without further purification(1.11 g, 5.04 mmol).