Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:17][CH:16]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1ccc(Br)cc1
Product: O=C(Nc1ccc(Br)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4-bromoaniline using the same procedure described in example 5.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11](OC)(OC)(OC)[CH3:12]>O>[Br:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: COC(C)(OC)OC
Reactant: NNc1ncc(Br)nc1Cl
Solvent: O
Product: Cc1nnc2c(Cl)nc(Br)cn12
Temperature: 130 °C

Procedure:
5-bromo-3-chloro-2-hydrazinylpyrazine 1′-1 (945 mg; 3.51 mmol) is dissolved in 12 ml trimethyl orthoacetate and heated up to 130° C. for 1 hour. The solution is diluted with water and extracted with EtOAc. The organic phase is then purified with flash chromatography: cHex/EtOAc=70%/30% to 55%/45% within 10 column volumes.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:16])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37].O>O1CCCC1>[Br:16][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:37])[N:6]2[C:7]=1[C:2]([NH2:1])=[N:3][CH:4]=[N:5]2
Reactant: Nc1ncnn2c(CCCCO)cc(Br)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnn2c(CCCCBr)cc(Br)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-1-ol (600 mg, 2.10 mmol) and triphenylphosphine (828 mg, 3.16 mmol) in tetrahydrofuran (15 mL) was added carbon tetrabromide (837 mg, 2.53 mmol). The reaction was stirred (0° C.) for 90 min and then was warmed to rt and stirred an additional 1 h. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4) and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 25 to 50% ethyl acetate in hexanes to afford 597 mg (82%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1 H), 6.62 (s, 1 H), 3.54 (t, 2 H), 2.84 (t, 2 H), 1.86-1.70 (m, 4 H); ES-MS m/z 347.2 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (3.0 g, 22.03 mmol) in 45 mL methylene chloride was added 3,4-dihydro-2H-pyran (5.0 mL, 54.8 mmol) and pyridinium p-toluenesulfonate (0.55 g, 2.19 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with three portions of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated. Silica gel flash chromatography of the residue (10% ether/hexanes to 20% ether/hexanes) afforded 4.35 g of the title compound of Step A. MS 221.1 (M+1)+
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(NCCCCCCOC2CCCCO2)cc1
Product: CC(C)c1ccc(N(CCCCCCOC2CCCCO2)C(=O)C2CCCc3ccccc32)cc1
Yield: 33.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and (4-isopropylphenyl)[6-(tetrahydropyran-2-yloxy)hexyl]amine (2.0 g) as starting materials, N-(4-isopropylphenyl)-N-[6-(tetrahydropyran-2-yloxy)hexyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.0 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 9, N-(6-hydroxyhexyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.4 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (135 mg, 70.2% yield) as white crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)[C:34](=[CH:42][C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][C:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])([CH3:53])[CH3:52])[C:33]1=[O:59])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:59])[C:34]3([CH:42]([C:43]4[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=4[O:50][C:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])([CH3:53])[CH3:52])[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 29.2 %

Procedure:
To a toluene solution (50 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (77 mmol) was added E/Z 6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (8 g, 15.44 mmol). Then the reaction mixture were heated at 130° C. for 2. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (2.7 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O1CCCC1.C([Li])CCC.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[C:31]([C:39]([CH3:43])([CH3:44])[C:40]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[O:41])[CH:30]=[C:29]([C:28]([F:45])([F:27])[F:46])[CH:34]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(Cl)cc1-c1cccnc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2.77 g (11.9 mmol) (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine in 120 ml tetrahydrofuran 7.8 ml (12 mmol) of a 1.6 M solution of n-butyllithium in hexanes was added dropwise at −78° C. After 30 min. 4.2 g (13 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was stirred at −78° C. for 5 min. and allowed to warm to room temperature during a period of 1 h. Dilution with 2 M aqueous sodium carbonate solution was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with 2 M aqueous sodium carbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 4.8 g (78%) of the title compound as an off-white solid.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(OC([NH:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][N:23]=1)=S)=O)C>C(O)C>[Cl:28][C:26]1[CH:25]=[CH:24][N:23]2[N:6]=[C:19]([NH2:18])[N:21]=[C:22]2[CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)ccn1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1nc2cc(Cl)ccn2n1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (5.35 g, 77.0 mmol, Eq: 5) and N-ethyldiisopropylamine (5.97 g, 8.07 ml, 46.2 mmol, Eq: 3) in ethanol (80 ml) was stirred for a few minutes at 25° C., then the mixture was added to 1-ethoxycarbonyl-3-(4-chloro-pyridin-2-yl)-thiourea (4.0 g, 15.4 mmol, Eq: 1.00) and the resulting mixture was refluxed for 2.5 days (over the weekend). The crude material was applied on SiO2 and purified by flash chromatography over a 20 g SiO2 column using ethyl acetate 100% as eluent affording 7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.03 g/78.2%) as a white solid. MS: m/e=169.1 (M+H+), mp: 189-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([C:28]#[N:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1>C(O)=O.O.[Pt](=O)=O>[NH2:29][CH2:28][C:19]1[C:18]([CH2:17][N:15]2[C:14](=[O:30])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[C:10]3=[N:16]2)=[CH:23][CH:22]=[C:21]([C:24]([F:25])([F:27])[F:26])[N:20]=1
Reactant: N#Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: O=[Pt]=O
Solvent: O
Solvent: O=CO
Product: NCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinonitrile (51 mg, 0.1 mmol) in formic acid (0.8 mL) and water (0.2 mL) was added platinum (IV) oxide (20 mg). The resulting suspension was stirred at 70° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3, water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The product was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.4 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.26 min, [M+H]+=511.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@H:30]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazole (180 mg, 0.262 mmol) synthesized in Example (35c) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.53 mL, 0.53 mmol) was added, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. Water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired compound (103 mg, yield 79%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH:12]=[CH:13][CH:14]=[C:6]12)=[O:4].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=[C:6]12)=[O:4]
Reactant: COC(=O)C1CCCCn2cccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCCCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 44 h

Procedure:
A solution of the resulting ester (1.2 g., 0.006 moles) in dry xylene (50 ml.) containing benzoyl chloride (1.5 g., 0.01 moles) is heated at reflux temperature, in a nitrogen atmosphere, for 44 hours. The solvent is removed in vacuo and the residue is purified by t.l.c. on silica gel (hexane-ethyl acetate, 3:1) to give a product in 50% yield which, when crystallized from acetone hexane, gives methyl-3-benzoyl-5,6,7,8-tetrahydro-9H-pyrrolo[1,2,a]azepine-9-carboxylate having a m.p. 98°-99° C.
Reaction SMILES: C([O:3]C(C=NC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(F)=CN=2)C=CC=1)=O)C.[F:30][C:31]1[C:32]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=2)=[N:33][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50]NC)=[O:47])[CH:39]=2)=[N:35][CH:36]=1>>[F:30][C:31]1[C:32]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=2)=[N:33][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][OH:3])=[O:47])[CH:39]=2)=[N:35][CH:36]=1
Reactant: CNCCNC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1)NCCO

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine, N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and N-methyl-ethylen-1,2-diamine were reacted to prepare 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.31 min.; purity: 94.7%; MS (m/e): 426.01 (MH+).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(CC)CC.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][O:16][S:26]([CH3:29])(=[O:28])=[O:27])[N:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(CO)co1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(COS(C)(=O)=O)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-methanol (326 mg, 1.33 mmol) in dry CH2Cl2 (8.0 mL) was treated at 0° C. with Et3N (0.24 mL, 1.70 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.67 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=1.05 min; [M+H]+=322.25.
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.ClCCl>[N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: OCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl imidazo[1,2-a]pyridine-2-carboxylate (1.5 g, 7.9 mmol) was dissolved in diethyl ether (30 mL) and dichloromethane (20 mL). Lithium aluminum hydride (450 mg, 11.8 mmol) was added at 0° C., and the mixture was stirred 3 hours at room temperature. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, imidazo[1,2-a]pyridin-2-ylmethanol was obtained as a yellow oil (527 mg, 45% yield) and used in the next step without purification; 1H NMR (400 MHz, CDCl3): δ 4.86 (s, 2H), 6.76-6.80 (m, 1H), 7.15-7.20 (m, 1H), 7.55-7.58 (m, 2H), 8.09 (d, J=6.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8]O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([NH2:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(OCCO)cc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)CCOc1ccc(N)c([N+](=O)[O-])c1

Procedure:
2-(4-amino-3-nitro-phenoxy)-ethanol Compound 18a (0.5 g, 2.52 mmol) was treated with TBSCl (0.42 g, 2.52 mmol) and imidazole (0.173 g, 2.52 mmol) in DMF (10 mL) at room temperature overnight. DMF was removed under vacuum and the residue was diluted with AcOEt, washed with H2O and saturated aqueous NH4Cl and dried over Na2SO4. The solvent was evaporated to dryness to provide 4-[2-(tert-butyl-dimethyl-silanyl)-ethoxy]-2-nitro-phenylamine Compound 18b (0.787 g) as a golden solid. LCMS single peak, 3.93 min, MS (ESI) m/z 313.2 (M+H+). 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1 H), 7.00 (d, 1 H, J=9.0 Hz), 6.66 (d, 1 H, J=9.0 Hz), 3.94-3.84 (m, 4 H), 0.81 (s, 9 H), −0.01 (s, 6 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>O1CCOCC1>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Reactant: COCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCOCCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and diethylene glycol monomethyl ether in dioxane. ES-MS m/e (%): 511 (M+Na+, 13), 489 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[C:24]([CH:26]=[C:27]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25].N12CCCN=C1CCCCC2>C(#N)C>[C:24]([CH2:26][C:27]1([N:22]2[CH:23]=[C:19]([C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=34)[CH:20]=[N:21]2)[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1)#[N:25]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)c(F)cnc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3c(F)cnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 5-fluoro-4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.02 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.168 g, 6.02 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8996 mL, 6.02 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc/hexanes) to give 3.05 g (96.3%) of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC/MS found: 527.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:12]=[O:13])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([CH:12]([OH:13])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:22])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(=O)Nc1cccc(F)c1C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(F)c1C(O)c1ccccc1C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
100 mg (0.83 mmol) N-(3-fluoro-2-formyl-phenyl)-acetamide are dissolved in 4 ml of tetrahydrofuran and cooled to −78° C. Then at this temperature 1.66 ml (3.3 mmol) of a 2 M solution of o-tolylmagnesium bromide in diethyl ether are added. This reaction mixture is thawed to ambient temperature overnight with stirring. Then the reaction mixture is stirred into 30 ml dist. water and extracted three times with 10 ml of ethyl acetate. The organic phase is dried with MgSO4, the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).