Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(O)=[O:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:2])[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNC1
Agent: Cl
Product: O=C(c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCC1
Yield: 84.5 %

Procedure:
In the same manner as in step c) in Example 3, 594 mg of the title compound was prepared from 644 mg of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 168 mg of azetidine hydrochloride.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])#[N:12].CCN(C(C)C)C(C)C.Cl>C1COCC1>[C:11]([CH:13]([CH2:1][C:2](=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:12]
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
A solution (1 M) of phenacyl bromide in THF was added dropwise to a solution (5.5 M) of methyl cyanoacetate (1.1 eq.) and DIEA (2.4 eq.) in THF at RT. The resulting solution was stirred at RT for 20 h then the mixture was filtered and the filtrate was concentrated in vacuo to obtain an oil that was treated with little portions of aqueous HCl (1 N). The organic phase was washed with brine, dried and concentrated affording the title compound (97%) as an oil that solidified when stored in the fridge.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C[C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[S:16][CH:12]=2)[N:6]2[C:5]=1[CH:10]=[CH:9][CH:8]=[N:7]2
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Reactant: Brc1cnc2cccnn12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnc3cccnn23)cs1
Temperature: 100 °C

Procedure:
3-Bromoimidazo[1,2-b]pyridazine (700 mg, 3.53 mmol), methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.04 g, 3.89 mmol), Pd2(dba)3 (324 mg, 0.353 mmol), tricyclohexylphosphine (248 mg, 0.884 mmol), aqueous tribasic potassium phosphate (2.54 mL, 12.0 mmol, 1.27 M), and 1,4-dioxane (17.7 mL) were placed in a sealed tube and purged with nitrogen for 5 minutes. The solution was heated to 100° C. for 1.5 h, after which the reaction was cooled to room temperature. Saturated aqueous sodium bicarbonate was added to the mixture. The aqueous layer was then extracted with ethyl acetate (×3). The combined organic layers were then dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.70 (d, 1H); 8.68 (s, 1H); 8.54 (s, 1H); 8.42 (s, 1H); 8.22 (d, 1H); 7.31 (dd, 1H); 3.86 (s, 3H). LRMS (APCI) calc'd for (C12H9N3O2S) [M+H]+, 260.0. found 260.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)(=O)=O.[C-:32]#[N:33].[K+].C(OCC)(=O)C>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)#[N:33]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)C(F)(F)F)C(=O)OC2
Reactant: [C-]#N
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(C#N)c2c(c(C)c1OC)COC2=O
Reaction time: 18 h
Yield: 94.1 %

Procedure:
A nitrogen-flushed mixture of 5.8 g (12.4 retool) of methyl (E)-6-(1,3-dihydro-4-trifluoromethylsulfonyloxy -6-methoxy-7-methyl-3-oxoisobenzofuran5-yl)-4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potassium cyanide, and 1.11 g (0.96 mmol) of tetrakis(triphenylphosphine) palladium in 100 ml of 1,4-dioxane was heated at reflux for 18 hours. Upon cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was washed with water six times, with brine once, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting solid was stirred with hexane for 18 hours and then filtered off. This solid was further purified by silica gel chromatography using 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(1,3-dihydro-4-cyano-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4hexenoate, mp 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>C1(C)C=CC=CC=1>[Cl:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:21][CH:22]=1
Reactant: O=C=NCCCCl
Reactant: Cc1cccc(N2CCN(CCc3ccc(N)cc3)CC2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3ccc(NC(=O)NCCCCl)cc3)CC2)c1

Procedure:
11.3 gm (38.5 millimols) of N-(p-amino-phenethyl)-N'-(m-tolyl)-piperazine, 4.6 gm (38.5 millimols) of 3-chloropropyl-isocyanate and 120 ml of toluene were admixed with each other, accompanied by gentle agitation, and the mixture was allowed to react for two hours and was then vacuum-filtered, yielding as the filter cake 90% of theory of N-[p-(3-chloropropyl-ureido)-phenethyl]-N'-(m-tolyl)-piperazine, m.p. 168°C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9]O.O>C(Cl)Cl>[Br:2][CH2:9][C:8]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]=1[O:6][CH3:5]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC)c(CBr)c1
Yield: 173.4 %

Procedure:
A solution of phosphorous tribromide (5.74 ml, 60.4 mmol) in anhydrous DCM (90 ml) was added over 20 min to a cooled, stirred solution of 2,5-dimethoxybenzyl alcohol (25.0 g, 148.8 mmol) in DCM (180 ml), maintaining the temperature between −5° C. and 0° C. Following the addition, the reaction was stirred at this temperature for a further 20 min. when water (200 ml) was added. After separation of the layers, the organic was washed with water (3×200 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. The resulting crude product was crystallised from diethyl ether/heptane to afford 2-bromomethyl-1,4-dimethoxy-benzene (24.2 g, 72%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][CH2:29][CH2:30]O)[CH:24]=[C:25]([Cl:27])[CH:26]=1.[Br:32]Br.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]([Br:32])[CH2:29][CH3:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: BrBr
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCC(Br)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Triphenylphosphine (315 mg, 1.20 mmol) was added to a solution of 3-(3,5-dichlorophenyl)-propanol (200 mg, 0.98 mmol) in CH2Cl2 (20 mL). The reaction mixture was cooled to 0° C. and bromine (207 mg, 1.30 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. The reaction was poured into water and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (hexanes) to afford the title compound (134 mg). 1H NMR (400 MHz, CDCl3) δ7.21 (m, 1H), 7.08 (m, 2H), 3.37 (t, 2H), 2.74 (t, 2H), 2.13 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.CO.O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCNC(=O)NCCCNn1c(COCC)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCNC(=O)NCCCNn1c(COCC)nc2c(N)nc3c(c21)CCCC3
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.4 %

Procedure:
A solution of 1-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-3-ethylurea (0.700 g, 1.82 mmol) in 20 mL of TFA was treated with platinum (IV) oxide (0.413 g, 1.82 mmol). The mixture was placed under an atmosphere of nitrogen (3.8×105 Pa) and shaken at ambient temperature. After 22 h, the reaction mixture was diluted with 50 mL of CHCl3 and 10 mL of MeOH and filtered through a pad of CELITE filter agent. The pad was rinsed with 20% MeOH in CHCl3 until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield a clear, colorless oil. The oil was suspended in 25 mL of H2O and treated with 50% NaOH until the pH of the liquid reached 13. A white solid precipitated. The solid was triturated in the basic solution for 15 min and then filtered to give a white solid. The solid was recrystallized from MeCN to yield 1-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-3-ethylurea (0.400 g) as white crystals. mp 189–191° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.31 (t, J=5.9 Hz, 1H), 5.83–5.79 (m, 3H), 5.74 (t, J=5.6 Hz, 1H), 4.61 (s, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.11–2.94 (m, 8H), 2.66 (t, J=5.8 Hz, 2H), 1.83–1.67 (m, 4H), 1.59 (p, J=6.9 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 158.4, 149.9, 149.3, 147.0, 137.6, 122.7, 105.5, 65.7, 63.3, 51.7, 37.5, 34.4, 32.5, 28.9, 23.2, 23.0, 22.4, 16.0, 15.3; MS (APCI) m/z 390 (M+H)+; Anal. Calcd for C19H31N7O2: C, 58.59; H, 8.02; N, 25.17; Found: C, 58.35; H, 8.30; N, 25.31.
Reaction SMILES: C(OCCCC)CCC.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.BrBr.[CH2:23]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[K+]>CO.O>[CH3:19][CH:18]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32]1)[CH:17]([OH:20])[C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCCCOCCCC
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 90 %

Procedure:
To 10 ml of di-n-butyl ether were added 6.0 g of 4'-hydroxypropiophenone. 6.6 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 7.5 g of 4-benzylpyridine, 4.0 g of potassium hydrogen carbonate, 1 ml of water and 50 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, the reaction mixture was treated in the same manner as described in Example 46, whereby 11.7 g (76.0%) of ifenprodil were obtained as white crystals.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=[O:15].[Na+].NC(N)=O.[OH-].[Na+]>S(=O)(=O)(O)O.O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu-]=O>[S:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:15])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=N[O-]
Reactant: Nc1ccc(N2CCSCC2)cc1
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: NC(N)=O
Solvent: O
Product: Oc1ccc(N2CCSCC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.34 g of 4-(p-aminophenyl)-tetrahydro-4H-1,4-thiazine are dissolved in 12 ml of 35 percent sulfuric acid, 12 g of ice are added thereto, a cold solution of 1.05 g of sodium nitrite in 12 ml of water is then slowly introduced under the surface and the mixture is stirred for 5 minutes at about 0°. Thereafter, there are added 60 mg of urea, a solution of 144 g of copper(II) nitrate trihydrate in 420 ml of water and finally while stirring vigorously 1.59 g of copper(I) oxide. The mixture is stirred for 5 minutes, adjusted to about pH 6 with sodium hydroxide solution and extracted three times with 600 ml of dichloromethane each time and once with 600 ml of dichloromethane/ethanol (4:1). The organic phases are washed twice with 300 ml of water each time, dried over sodium sulfate and evaporated. The crude product is chromatographed on 400 g of silica gel with dichloromethane which contains 5% acetone. The material obtained is recrystallized from dichloromethane/methanol/ether, whereby there is obtained p-(tetrahydro-4H-1,4-thiazin-4-yl)phenol of melting point 155°-157°.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][C:46]1[CH:68]=[CH:67][C:49]2[NH:50][C:51](=[C:53]([C:57]3[N:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)[C:54]([NH2:56])=[O:55])[S:52][C:48]=2[CH:47]=1>CN(C=O)C.CC(=O)OCC>[C:2]([O:6][C:7]([NH:9][CH2:10][C:11]([NH:45][C:46]1[CH:68]=[CH:67][C:49]2[NH:50][C:51](=[C:53]([C:57]3[N:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)[C:54]([NH2:56])=[O:55])[S:52][C:48]=2[CH:47]=1)=[O:13])=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: NC(=O)C(=C1Nc2ccc(N)cc2S1)c1nccc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(c1)SC(=C(C(N)=O)c1nccc(C(F)(F)F)n1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 76A was prepared from compound 32A as follows. To a solution of N-(tert-butoxycarbonyl)glycine hydrochloride (20 mg) in DMF (5 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg), triethylamine (388 μL, 3.88 mmol), and 2-[6-aminobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (141 mg). The mixture was stirred at room temperature for 1 hr, then poured into EA (50 mL). The EA layer was washed three times with 10% aqueous sodium bicarbonate (30 mL each), and three times with water (15 mL each), then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-{6-[(tert-butyloxycarbonylamino)acetylamino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide as a brown foam. 2-{6-[(Tert-butyloxycarbonylamino)-acetylamino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (80 mg, 156 mmol) was dissolved in 4N hydrogen chloride in dioxane (5.0 mL, 20 mmol), and the mixture stirred at room temperature for 2 hr. The mixture was concentrated to give 2-{6-[(2-aminoacetyl)-amino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (50 mg) as a beige solid. Other compounds with an amide side-chain may be similarly prepared from compound 32A.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:33][C:30]4[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: ClCc1ccncc1
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3ccncc3)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 4-picolyl chloride hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 25% ethyl acetate in methylene chloride. Mass spectrum: m/e 430 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=[CH:11][S:10]3)=[N:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].CCN(CC)CC>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:16]([NH:15][C:14]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[C:5]1[S:6][C:2]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:3][N:4]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C#Cc1ccccn1
Reactant: CC(C)(C)Nc1c(-c2ncc(Br)s2)nc2sccn12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)Nc1c(-c2ncc(C#Cc3ccccn3)s2)nc2sccn12
Yield: 16.7 %

Procedure:
A mixture of 235 mg (0.66 mmol) 6-(5-bromothiazole-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine, 22 mg (0.033 mmol) bis(triphenylphosphine)-palladium-(II)-chloride, 12 mg (0.066 mmol) copper-(I)-iodide, 80 μl (0.79 mmol) 2-ethynylpyridine and 731 μl (5.28 mmol) NEt3 in DMF (2 ml) was heated in the microwave (Biotage Initiator) for 10 min to 120° C. The reaction solution was diluted with water and extracted several times with AE. The collected organic phases were washed with brine and dried over MgSO4. After filtering and removal of the solvent in a vacuum, a CC (1.TBME, 2.MeOH) was performed with the residue, whereby 43 mg (0.11 mmol, 17%) N-tert-butyl-6-(5-(pyridine-2-ylethynyl)thiazole-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained.
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH2:6][CH2:7][NH2:8])(=O)C.[OH-].[K+].O.C(Cl)(Cl)Cl>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][NH2:8])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)(CCN)c1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
30.1 g of 3-acetoxy-3-(4'-fluoro-4-biphenylyl)-1-butylamine [obtainable from 3-bromo-3-(4'-fluoro-4-biphenylyl)-1-butylamine and potassium acetate] are boiled for 2 hours with 20 g of KOH in 500 ml of methanol, and the mixture is worked up with water and chloroform to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutylamine, m.p. 144°-146°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[CH2:28]([O:30][C:31](=[O:41])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=1)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:28]([O:30][C:31](=[O:41])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)=[CH:36][N:35]=1)[CH3:29]
Reactant: CCOC(=O)C=Cc1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (222 mg, 0.585 mmol), ethyl-3-(5-bromopyridin-2-yl)prop-2-enoate (101 mg, 0.393 mmol), PdCl2(dppf) (62.9 mg, 0.086 mmol), sodium carbonate (2 M, 0.40 mL, 0.800 mmol), and dioxane (2.00 mL) was purged and flushed with Ar(g) (3×) and irradiated in a microwave reactor for 10 minutes at 100° C. The reaction mixture was further irradiated with microwave at 150° C. for another 10 minutes. The mixture was filtered, concentrated under reduced pressure and the residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford ethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]prop-2-enoate. C22H20F3N4O2 [M+H]+ 429. found 429. 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J=2.1 Hz, 1H), 8.64 (d, J=4.9 Hz, 1H), 7.93-7.85 (m, 2H), 7.73 (d, J=15.7 Hz, 1H), 7.64 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 7.03 (d, J=4.9 Hz, 1H), 6.94 (d, 1H), 4.28 (q, J=7.1 Hz, 2H), 2.42 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:26])[C:8]1[C:17]2[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)(C)(C)C.Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=2)=[C:19]([NH:7][C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:24]=1
Reactant: Cc1ccc(O)c(N(C(=O)OC(C)(C)C)c2ccnc3nc(C)ccc23)c1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(COc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
A solution of Example 104B (37 mg, 0.1 mmol), N-(4-chloromethyl-phenyl)-acetamide (22 mg, 0.12 mmol), cesium carbonate (130 mg, 0.4 mmol) and tetrabutylammonium iodide (0.001 g) in DMF (1 ml) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted by ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was added dichloromethane (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The solvent was evaporated and the crude residue was purified by chromatography on silica eluting with 2% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound as a trifluoroacetic acid salt (11 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.00 (s, 3 H) 2.31 (s, 3 H) 2.74 (s, 3 H) 5.05 (s, 2 H) 6.36 (d, J=6.99 Hz, 1 H) 7.12 (d, J=8.46 Hz, 2 H) 7.25 (m, 3 H) 7.40 (d, J=8.46 Hz, 2 H) 7.73 (d, J=8.46 Hz, 1 H) 8.43 (d, J=6.99 Hz, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.89 (s, 1 H) 10.65 (s, 1 H) 14.25 (s, 1 H); MS (ESI+) m/z 413 (M+H)+.