Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]([OH:14])=[O:13]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)C=Cc1cc(F)c(F)cc1F
Solvent: CC(=O)O
Product: O=C(O)CCc1cc(F)c(F)cc1F
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
3-(2,4,5-Trifluorophenyl)acrylic acid (3.50 g, 17.3 mmol) was dissolved in glacial acetic acid (40 mL) and treated with active carbon (˜0.5 g). The mixture was stirred for 20 min, the carbon filtered off and washed with glacial acetic acid (20 mL). To the resulting solution Pd on carbon catalyst (0.45 g, 10% Pd) was added and the mixture was stirred under hydrogen at atmospheric pressure overnight. The suspension was filtered and concentrated in vacuo. Residual acetic acid was removed by addition of a small volume of toluene followed by concentration in vacuo. The resulting oil crystallized upon standing and this material was dried in vacuum at 50° C. to give 3.34 g (95%) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]([CH2:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methanesulphonyl chloride (16.15 g) was added dropwise to a stirred solution of 3-phenoxy-1-propanol (17.81 g) and triethylamine (23.78 g) in dry dichloromethane (120 ml) at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and then washed successively with 2N hydrochloric acid (100 ml), water (100 ml), 8% sodium bicarbonate solution (100 ml) and brine (100 ml). The solution was dried and evaporated in vacuo to give an oil which solidified on standing to give the title compound (25.88 g) as a waxy solid. T.l.c. (diethyl ether) Rf 0.50.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.[CH3:20]I>C(O)C>[CH3:20][NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Reactant: CI
Solvent: CCO
Product: CNc1ccc2c(c1)sc1nc(-c3ccccc3)cn12
Yield: 9.6 %

Procedure:
To 50 ml of ethanol were added 500 mg of 7-amino-2-phenylimidazo[2,1-b]benzothiazole, 265 mg of methyl iodide and 260 mg of potassium carbonate anhydride and while stirring vigorously, the mixture was refluxed for 2 days. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was extracted with 50 ml of ethyl acetate and the extract was washed with water, dried with anhydrous magnesium sulfate, and then the extract was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: toluene:ethyl acetate=4:1) and the obtained crystals were recrystallized from toluene to provide 50 mg of 7-methylamino-2-phenylimidazo-[2,1-b]benzothiazole.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1[O:10][C:11](=O)[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:32][C:11](=[O:10])[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 19.5 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 11.1 parts L-leucine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude dipeptide is then subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonylglycyl-L-leucine benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[CH2:22][C:23](Cl)=[O:24]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH:11][C:23](=[O:24])[CH2:22][C:15]1[C:16]([F:21])=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])[CH3:2]
Reactant: O=C(Cl)Cc1c(F)cc(F)cc1F
Reactant: CCOC(=O)c1cccnc1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1NC(=O)Cc1c(F)cc(F)cc1F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
2-Aminonicotinic acid ethyl ester (2.4 g) was suspended in dry toluene (50 ml). To the stirred suspension, 2,4,6-trifluorophenylacetyl chloride (3.0 g) in dry toluene (20 ml) was added. The resulting suspension was heated to reflux for 8 hours. The reaction mixture was cooled to ambient temperature, diluted with diethyl ether (100 ml), washed with water and brine, and the organic layer was dried over magnesium sulphate. The solvent was evaporated to give 2-[2-(2,4,6-trifluorophenyl)-acetylamino]-nicotinic acid ethyl ester as a yellow solid (4.5 g, 93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)(C)C.O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26]([F:37])([F:36])[F:25])[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[CH3:24])=[O:23]
Reactant: OB(O)c1cnccc1C(F)(F)F
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cn3nc(-c4cnccc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 24.3 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.034 g, 0.1 mmol), [4-(trifluoromethyl)-3-pyridyl]boronic acid (0.038 g), bis(triphenylphosphine)palladium(II) dichloride (7 mg), Na2CO3 (0.032 g), and isopropanol-water (1 mL, 3:1). The mixture is heated at 80° C. for 16 hr, cooled, concentrated, taken up in 1:1 EtOAc and CH2Cl2, filtered, concentrated onto celite and purified by silica gel chromatography (10-100% EtOAc in Hexanes) to give the title compound (0.011 g, 25% yield). LCMS m/z=454.5 [M+H]+, tR=2.47 min. (compound same as Example 364)
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C(=O)O)s1
Reactant: C=CCCCCN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCCCNC(=O)c1cnc(SCC)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 mole of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 1-aminohex-5-ene in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured in 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-(hex-5-enylaminocarbonyl)thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]2[C:11]=1[CH2:12][CH2:13][NH:14]2>C(Cl)Cl.CO>[Br:8][C:18]1[C:10]([F:9])=[C:11]2[C:15](=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=1)[NH:14][CH2:13][CH2:12]2
Reactant: O=C(O)c1ccc(F)c2c1NCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cc(Br)c(F)c2c1NCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (40 mg, 0.23 mmol) was added to a solution of 4-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (36 mg, 0.14 mmol) in DCM (3 mL) and MeOH (1 mL). The reaction was stirred at room temperature overnight and filtered. The filtrate was evaporated, and the residue was purified by flash chromatography, giving the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH3:18]I>>[CH3:18][N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: COc1cc2ccccc2c2c1C(C)(C)CN2
Reactant: CI
Product: COc1cc2ccccc2c2c1C(C)(C)CN2C

Procedure:
1-Amino-3-methoxynapthalene 18 was acetylated with 2-bromo-2-methylpropionyl chloride according to the general amino group acylation procedure described above in Example 2 to give compound 23. Compound 23 was cyclized by the Friedel-Crafts cyclization procedure described above in Example 2 to give compound 24. Next, compound 24 was reduced with 3 equivalents LAH in THF to give the 4-methoxybenzoindoline 25. Compound 25 was alkylated using the general amino group alkylation procedure described above in Example 3 using methyl iodide as the alkylating agent to give a N-methyl-3,3-dimethyl-4-methoxybenzoindoline intermediate 26 (1HNMR: CD3Cl d 8.07 (bd, 1 H, J=8.4 Hz), 7.69 (bd, 1 H, J=8.1 Hz), 7.33 (bt, 1 H, J=7.8 Hz), 7.22 (bt, 1 H, J=8.1 Hz), 6.70 (s, 1 H), 3.92 (s, 3 H), 3.32 (s, 2 H), 3.32 (s, 3 H), 1.44 (s, 6 H). Subsequent methoxy group deprotection of compound 26 by the general boron tribromide procedure described in Example 1 resulted in the N-methyl-3,3-dimethyl-4-hydroxy-benzoindoline 27.
Reaction SMILES: [ClH:1].CO.[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][C:7]=1[CH2:8][NH:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1.[H][H]>[Pt]>[ClH:1].[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][C:7]=1[CH2:8][NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][C@H:11]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1-c1ccccc1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Yield: 25.2 %

Procedure:
To a 250 mL Parr bottle were charged 5.1 gms 5% Pt/C, 85 mL 1.0M HCl/CH3OH, and 1.7 grams of 3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenylpyridine. The reaction mixture was hydrogenated at 46-50 psi hydrogen at ambient temperature for 9.5 hours. After filtering the reaction mixture over Celite® and washing the cake with methanol, the filtrate was concentrated to a white solid. This material was repulped in acetonitrile at ambient temperature, filtered, and dried to yield 0.52 grams (25.2%) of a white material. The identity of this material was establishd by high resolution NMR.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:52]=[CH:51][C:50]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])=[CH:49][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:48]=[CH:49][C:50]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])=[CH:51][CH:52]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccc(NS(C)(=O)=O)cc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 62 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (94 mg, 0.32 mmol), sodium carbonate (33 mg, 0.32 mmols), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (31 mg, 0.04 mmol) and 3 ml 1,2-dimethoxyethane and 0.75 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 65 mg (62% yield, 82% purity) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[N:13][NH:14][C:15]([NH2:17])=[O:16])[CH2:2][P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1
Reactant: COP(OC)OC
Product: COP(=O)(CC(COc1ccc(Cl)cn1)=NNC(N)=O)OC
Reaction time: 2 h

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane (322 mg.) and trimethyl phosphite (720 mg.) were mixed and heated at 70°-100° C., with stirring, for 11/2 hours. The mixture was evaporated to dryness, finally under high vacuum, to give dimethyl 3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropylphosphonate, RF = 0.15 (5% v/v methanol in ethyl acetate), the required starting material. What we claim is:
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:14]2[CH:13]=[C:12]([N:15]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5](B1OC(C)(C)C(C)(C)O1)=[CH:6][CH:7]=2.I[C:41]1[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][N:42]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:47][C:44]1[CH:45]=[CH:46][C:41]([C:5]2[CH:4]=[C:3]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([N:15]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)[C:16]5[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=5)=[CH:13][C:14]=4[C:2]3([CH3:1])[CH3:39])=[CH:7][CH:6]=2)=[N:42][CH:43]=1
Reactant: Brc1ccc(I)nc1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(C)(C)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(C)(C)c2cc(-c4ccc(Br)cn4)ccc2-3)cc1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of 9,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N,N-di-p-tolyl-9H-fluoren-2-amine (Compound 33) (5.0 g, 9.7 mmol), 2-iodo-5-bromo-pyridine (8.26 g, 29.1 mmol), Pd(PPh3)4 (0.56 g, 0.48 mmol) and K2CO3 (5.36 g, 38.8 mmol) in dioxane/water (65 mL/13 mL) was degassed and heated at about 90° C. overnight. The resulting mixture was worked up with ethyl acetate and brine. The organic phase was dried over Na2SO4, loaded on silica gel, purified by flash column (hexanes/dichloromethane 5:1 to 1:3 to dichloromethane). The desired fraction was collected, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (Compound 34) (4.085 g, in 77% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:37].[Na+]>C(O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[N:15]4[C:11]([S:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[O:37])[NH2:2])[CH:4]=3)[CH:22]=[CH:21][N:20]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C#N)c4)nc4sccn34)n2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C(N)=O)c4)nc4sccn34)n2)C1
Temperature: 75 °C
Yield: 82.7 %

Procedure:
To a solution of tert-butyl (3R)-3-({4-[6-(3-cyanophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (0.204 g, 0.407 mmol) in ethanol (5 mL) was added 25% aqueous sodium hydroxide (0.072 mL, 0.448 mmol). The mixture was heated at 75° C. for 20 hours. Solvent was removed to dryness. Residue was taken into dichloromethane (20 mL), washed with water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane to afford 0.175 g (83%) of the title compound as an off-white solid. M.p.=161-165° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.14 (s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H). 7.54(t, J=7.6 Hz, 1H), 7.44 (d, J=4.4 Hz, 1H), 7.30-7.14 (bs, 2H), 7.15 (d, J=6.8 Hz, 1H), 6.33 (d, J=5.2 Hz, 1H), 3.96 (bs, 1H), 3.81-3.77 (m, 1H), 3.68 (bs, 1H), 2.94-2.90 (m, 2H), 2.00-1.97 (m, 1H), 1.80-1.77 (m, 1H), 1.59-1.53 (m, 1H), 1.46-1.40 (m, 1H), 1.34 (s, 9H); LCMS: 520 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][C:3]=1[OH:17].[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=S)=[CH:20][CH:21]=[CH:22][CH:23]=1>C(O)C>[CH3:8][C:7]1[C:2]2[N:1]=[C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:27])[O:17][C:3]=2[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: Cc1ccccc1N=C=S
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cc(O)c1N
Solvent: CCO
Product: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Reaction time: 7 h
Yield: 69.5 %

Procedure:
A mixture of t-butyl 4-amino-3-hydroxy-5-methyl-phenylacetate (0.38 g, Reference Example 10) in ethanol (10 mL) and o-tolylisothiocyanate (0.24 g) was stirred for 7 hours, then left to stand over night and then evaporated. The residue was dissolved in ethanol (10 mL) and the solution was treated with dicyclohexylcarbodiimide (0.36 g). This mixture was heated at reflux temperature for 2 hours and then evaporated. The residual gum was dissolved in dichloromethane (15 mL) and the solution was treated with trifluoroacetic acid (4.75 mL). After standing at room temperature for 3 hours the mixture was evaporated and the residue was dissolved in diethyl ether. This solution was extracted twice with saturated sodium bicarbonate solution and the pH of the combined aqueous extracts was adjusted to 1-2 by addition of dilute hydrochloric acid. This solution was then extracted with ethyl acetate and the extract was washed with brine, then dried and then evaporated to give the title compound (0.33 g) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](CCC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.[CH3:46][N:47]=[C:48]=[S:49]>C(Cl)Cl>[CH3:46][NH:47][C:48]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[N:10]=[C:11]2[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=2[O:43][CH2:44][CH3:45])=[O:22])[CH2:24][CH2:25]1)=[S:49]
Reactant: CN=C=S
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=S)NC)CC1
Reaction time: 3 h

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (279 mg, 0.47 mmol, example 8A) was dissolved in methylene chloride (3 mL) and methylisothiocyanate (64 uL) was added. After stirring 3 h, the reaction mixture was concentrated to dryness. Purification of the crude residue by flash chromatography (silica gel) eluting with ethyl acetate and hexanes gave 4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carbothioic acid methylamide (195 mg). LR-MS: 664.4 [(M+H)+].
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[Cl:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:30][C:29]1[CH:28]=[CH:27][C:26]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:25][C:24]=1[O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-benzyloxy-4-chlorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17ClN4O, 401. Found, 401.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-valine (10.86 g) and L-proline benzyl ester hydrochloride (12.09 g) in DMF (50 ml) were added HOBT (6.76 g) and WSCD (7.76 g) under ice-bath cooling. After being stirred at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 ml) and washed with 5% aqueous citric acid (200 ml) saturated aqueous sodium bicarbonate (200 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-L-valyl-L-proline benzyl ester (20.06 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Combine (5,6-dichloro-pyridin-3-yl)-methanol (3.05 g, 17.11 mmol) and manganese dioxide (37.2 g, 427.9 mmol) in CH2Cl2 (25 mL). Stir the reaction mixture at rt overnight. Filter the reaction mixture through Celite® washing with CH2Cl2 (2×10 mL). Concentrate the filtrate and dry under vacuum to provide the title compound (1.44 g, 48%).