Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([CH3:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[NH:17][C:18](=[O:20])[CH3:19]>>[C:18]([NH:17][C:16]1[CH:15]=[C:14]([N:13]([CH3:12])[CH3:24])[CH:23]=[CH:22][C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])(=[O:20])[CH3:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(=O)Nc1cccc(N(C)C)c1
Product: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
Condensation of phthalic anhydride and m-(dimethylamino)acetanilide by the method of part A of Example 1 affords 2-(2-acetamido-4-(dimethylamino)benzoyl)benzoic acid (II: Y'2 = CH3CONH, Y'4 = (CH3)2N, Z4 = Z'5 = Z'6 = Z7 = H).
Reaction SMILES: [C:1](NC(=O)CCCCC)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.C1C=C2C(OC3(C4C(=CC(O)=C(CN(CC(O)=O)CC(O)=O)C=4)OC4C3=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=4)C2=CC=1)=[O:31]>>[OH:31][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)=[O:15]
Reactant: CCCCCC(=O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C(O)CN(CC(=O)O)Cc1cc2c(cc1O)Oc1cc(O)c(CN(CC(=O)O)CC(=O)O)cc1C21OC(=O)c2ccccc21
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Liposomes were bound to adherent ECV304 cells via a biotin-streptavidin linkage. To this end DODAP/MeO-suc-AAPV-DOPE (1:1 mol:mol) liposomes were prepared with 0.3 mol % N-biotinyl caproylamine-PE (N-biotinyl-cap-PE) as well as fluorescent lipid probes or with encapsulated calcein. ECV304 cells that had been plated on glass coverslips in tissue culture plates were washed with HBSS buffer and then incubated sequentially at room temperature with biotin-wheat germ agglutinin (WGA) (20 ug/ml, obtained from Pierce, Rockford, Ill.) and streptavidin (40 ug/ml, obtained from Molecular Probes, Eugene, Oreg.) prepared in HBSS, 30 min/treatment. Cells were washed after each treatment. Liposomes were treated with or without elastase as described above. Certain aliquots of pretreated DODAP/MeO-suc-AAPV-DOPE (1:1 mol/mol) liposomes were freeze/thawed after dialysis and prior to addition to cells to release the liposomal contents. Such freeze/thawed liposomes were exposed to liquid nitrogen/37° C. water bath for 5 cycles. Self-quenching of calcein was reduced by approximately 85% (maximal FDQ determined by detergent solubilization) after freeze/thawing, indicating release of encapsulated calcein. In all cases, 50-100 nmol of liposomes were added to confluent ECV304 cell monolayers (1×105 cells/well of 24 well plate) and incubated in HBSS for 30 min at room temperature to promote N-biotinyl cap-PE binding to streptavidin. Unbound liposomes were removed by repeated washes. After the final wash, fresh HBSS buffer was added to all wells and cells were incubated at 37° C. for given times. Fluorescence was quantitated as described above. Calcein fluorescence was excited with the 488 nm line of a krypton/argon laser and observed at 522 nm emission
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.C[Si]([N-:14][Si](C)(C)C)(C)C.[Li+].[ClH:20]>C(OCC)C>[ClH:20].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:14])=[NH:8])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(C(=N)N)cc1
Reaction time: 2 h

Procedure:
To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl ether was added 23 g of solid lithium bis(trimethylsilyl)amide at ambient temperature. The mixture was stirred for 2 hours then hydrolysed with 10% HCl at 0° C. The mixture was stirred for an additional 30 minutes and then concentrated to dryness to yield 6 g of 4-methylbenzamidine hydrochloride which was used in the next step without further purification
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>>[F:14][C:13]([F:16])([F:15])[CH:12]([OH:17])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OC(CBr)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(OCC(O)C(F)(F)F)cc1
Yield: 84 %

Procedure:
The title compound is prepared analogously to Example 12A from 4-hydroxybenzaldehyde and 3-bromo-1,1,1-trifluoropropan-2-ol.
Reaction SMILES: [CH:1]1([N:6]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:21])[F:20])[CH:14]=3)[C:9](=[O:22])[C:8]([C:23](O)=[O:24])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=1>CN(C=O)C>[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH:66][C:23]([C:8]2[C:9](=[O:22])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:20])[F:21])[CH:14]=3)=[C:11]([CH3:12])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:24])=[N:62][N:61]=1
Reactant: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C1CCCC1
Reactant: Cc1nnc(CN)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CNC(=O)c2cn(C3CCCC3)c(C)c(-c3cccc(C(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9, 116 mg, 0.334 mmol), HBTU (140 mg, 0.369 mmol), DIPEA (116 μL, 0.668 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine (46 mg, 0.407 mmol) is added and the reaction mixture is stirred for 72 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 67 mg (45% of theory); ESI mass spectrum: [M+H]+=443; Retention time HPLC: 0.98 min (Z003_001).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:18]([C:20]1[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=1[O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][C@@H:28]([C:30]([O:32][CH3:33])=[O:31])[NH2:29])=[CH:25][CH:24]=1)#[N:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([NH:29][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[C:18]#[N:19])=[CH:35][CH:34]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccccc2C#N)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2C#N)cc1)NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 131 mg of N-Boc-2-(S)-methyl-(L)-proline, 190 mg 4-(2-cyanophenoxy)-phenylalanine, methyl ester hydrochloride, 297 mg PyBOP, and 4 mL of methylene chloride at 0° C. was added 300 μL of diisopropylethylamine via syringe. The reactants were allowed to warm to room temperature and said reaction was run over the weekend. The reaction was then diluted with methylene chloride, washed with water, 1N hydrochloric acid), saturated sodium bicarbonate solution, and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was purified via silica gel chromatography, eluted with 80% hexane:20% acetone to yield 263 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[C:41]=1B(O)O>>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[C:42]([OH:46])=[CH:43][CH:44]=[CH:45][C:40]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1c(O)cccc1F
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O)cccc5F)c4)nn23)CC1
Yield: 75 %

Procedure:
Prepared from (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (2-fluoro-6-hydroxyphenyl)boronic acid using the same procedure as intermediate 168 in 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.19-7.99 (m, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.46 (br. s., 1H), 7.25 (d, J=6.5 Hz, 1H), 6.92-6.74 (m, 3H), 6.13-5.78 (m, 2H), 5.59-5.47 (m, 1H), 5.39 (dd, J=17.2, 1.6 Hz, 1H), 5.20-4.99 (m, 1H), 4.00 (d, J=4.8 Hz, 2H), 3.76 (s, 3H), 2.72-2.54 (m, 3H), 2.05-1.87 (m, 3H), 1.79-1.64 (m, 1H), 1.35 (s, 3H), 1.25 (s, 9H). LCMS (M+1)=617.35.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:27][NH2:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:28][CH3:27])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with methylamine hydrochloride via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide (41 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 10.6 mg of 344. MS (Q1) 472.0 (M)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:23])([F:22])[F:24])[CH:4]=1)[C:28]([O:27][CH3:26])=[O:36]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[H][H]>O>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C=NO)cc1
Temperature: 25 °C

Procedure:
8.3 g of 4-nitrobenzaldoxime together with 100 ml of tetrahydrofuran are initially introduced into a stirred autoclave. 50 mg of FeCl2.4 H2O and 0.2 g of the catalyst from Example A1 are added to the solution. Hydrogenation is carried out at 120° C. and a hydrogen pressure of 20×105 pascals. When hydrogenation is complete, the mixture is cooled to room temperature, the reactor is rendered inert with nitrogen and the catalyst is filtered off. The solvent is distilled off to give, after chromatographic purification, 3.5 g (51% of theory) of 4-aminobenzaldoxime.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:13]1([CH2:12][CH2:11][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Equal molar amounts of triethoxysilane (5 mL) and styrene (3.1 mL) were combined with 10 microliters of a 5% platinum siloxane complex in xylene as shown by Karstedt, U.S. Pat. No. 3,775,452. After 30 minutes at 50° C. with stirring, there was obtained 45% yield of phenylethyltriethoxysilane based on gas chromatography analysis. The same reaction was repeated except that 0.25 g of β-cyclodextrin was added to the mixture. After 30 minutes at 50° C., there was obtained a 100% conversion to phenylethyltriethoxysilane based on gas chromatography analysis.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH4+].[O-][Mo:13]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>O>[Mo:13].[CH3:2][N:3]([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[Mo](=O)([O-])[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)c1ccccc1
Solvent: O
Product: [Mo]

Procedure:
N,N-dimethylaniline molybdate having a 2/1 molybdenum/N,N-dimethylaniline molar ratio was prepared in the presence of HCl as follows. 10 grams of N,N-dimethylaniline, 16.26 grams of a 37 wt.% aqueous HCl solution, and 250 ml water were dissolved together and heated to reflux in a 500 ml round-bottomed flask equipped with a water-cooled condenser. 28.05 grams of ammonium dimolybdate was dissolved in 52 ml hot water and then added to the first solution.
Reaction SMILES: O=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.O>C1(C)C=CC=CC=1>[S:33]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:8]=2)[NH:3]1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=S)N2
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a solution of 5-(2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1-methyl-pyrrole-2-carbonitrile (0.55 g, 1.8 mmol, 1 eq) in toluene (50 mL) was added Lawesson's reagent (0.47 g, 1.1 mmol, 0.65 eq) and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel gave the product as a white solid (0.32 g, 55%). 1H NMR (d6-DMSO, 500 MHz) δ 1.36–1.99 (m, 10 H), 3.7 (s, 3 H), 6.35 (d, 1 H, J=4.2 Hz), 7.05 (d, 1 H, J=4.2 Hz), 7.16 (d, 1 H, J=7.9 Hz), 7.44 (dd, 1 H, J=1.6, 8.1 Hz), 7.83 (d, 1 H, J=1.6 Hz), 12.75 (s, 1 H). MS (ESI) [M−H]−=320. Anal. calcd. for C19H19N3S: C, 70.99; H, 5.96; N, 13.07. Found: C, 68.69; H, 5.36; N, 12.27.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(#N)C>[ClH:2].[ClH:29].[Cl:29][C:30]1[C:31]([F:37])=[C:32]([NH:33][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][C@H:16]4[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4.0M HCl in dioxane (6.0 ml) was added to a stirred suspension of tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (3.21 g) and 3-chloro-2-fluoroaniline (0.98 ml) in acetonitrile (50 mL). The reaction mixture was heated at 80° C. and left at this temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/7N ammonia solution in methanol (97/3 to 95/5) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride as a solid (3.20 g); 1H NMR Spectrum: (DMSO d6) 1.56 (m, 2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m,1H), 3.20 (m, 1H), 3.95 (s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.63(s, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 444.02 g/mol.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[C:6]=2[N:7]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:34]=[CH:33][C:32]([NH:35][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[C:17]([F:20])([F:19])[F:18])[C:6]=4[N:7]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)[CH3:22]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: FC(F)(F)c1ccccc1-c1csc2cnc(Cl)nc12
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5ccccc5C(F)(F)F)c4n3)cn2)CC1
Yield: 61.3 %

Procedure:
N-(6-(4-Ethylpiperazin-1-yl)pyridin-3-yl)-7-(2-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine (19 mg, 61% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(2-(trifluoromethyl)phenyl)thieno[3,2-d]pyrimidine (20 mg, 0.64 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (13 mg, 0.064 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(Cl)Cl>CC(C)=O>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Nc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(N)nc2ccccc21
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1H-Benzoimidazol-2-ylamine (1 g, 7.5 mmol) was dissolved in acetone (30 mL) and powdered potassium hydroxide (2.12 g, 37.5 mmol) was added. The reaction was allowed to stir for several minutes at room temperature before (3-bromopropoxy)(tert-butyl)dimethylsilane (1.75 mL, 7.5 mmol) was added. After 1 hour, methylene chloride was added and the mixture was washed with water, brine and dried over magnesium sulfate. Upon concentration the crude product was dissolved in methylene chloride and purified by combiflash chromatography, methylene chloride to methylene chloride 6% MeOH gradient, to give 1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-benzo[d]imidazol-2-amine (0.400 g, 1.3 mmol).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][C:8]1[C:9]([CH2:23][OH:24])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:12]=1.[H-].[Na+].I[CH3:33]>O1CCCC1.O>[CH3:33][O:24][CH2:23][C:9]1[C:8]([O:7][C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([O:3][C:2]([F:1])([F:28])[F:29])[CH:5]=2)=[N:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[N:10]=1
Reactant: CI
Reactant: OCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole-4-methanol (i.e. the product of Example 5, Step I, 0.075 g, 0.18 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodium hydride (0.011 g, 0.28 mmol, 60% dispersion in oil). After 15 min., iodomethane (0.017 mL, 0.27 mmol) was added. The mixture was stirred at 23° C. for 1.75 h. The reaction mixture was diluted with water (20 mL), extracted with diethyl ether (3×15 mL), and washed with saturated aqueous sodium chloride solution (10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.045 g.) as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][O:12]2.C1C(=O)N([I:24])C(=O)C1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[I:24])[CH:14]=[CH:13][O:12]2
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccoc3n2)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a round bottom flask charged with 6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazole (5.0 g, 23 mmol; prepared using A from 6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazole [prepared according to WO2004110990A2, Example 1, Steps 1-3 using 2-bromo-1-(2,4-difluorophenyl)-ethanone in place of 2-bromo-1-(4-fluorophenyl)-ethanone]) and DMF (100 mL) was added a solution of NIS (5.4 g, 24 mmol) in DMF (20 mL) at ambient temperature. The reaction was allowed to stir at ambient temperature for about 1 h upon which time it was poured into water (800 mL). The resulting precipitate was filtered, washed with water (2×20 mL), and dried in a vacuum oven for about 16 h to provide the title compound (7.5 g, 95%) as a light yellow solid: LC/MS (Table 1, Method a) Rt=2.04 min; MS m/z/z: 347.0 (M+H)+.