Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[Br:39][CH:40]([CH2:47][CH3:48])[CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44]>C(#N)C>[Br-:39].[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:14]2[C:13](=[O:30])[CH:12]([CH2:11][CH2:10][CH:9]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:48][CH2:47][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCC(Br)CC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of 3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 3 ml of absolute acetonitrile. 300 mg of KF-alumina (1.15 mol/100 g) and 375 mg of (3-bromopentyl)-trimethylammonium bromide are then added. The reaction mixture is stirred at room temperature overnight and then filtered. The mother liquor is concentrated using a rotary evaporator and the residue is purified using a 5 g SiO2 cartridge (dichloromethane/methanol 4:1). The product is obtained as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC([O-])(C)C.[Na+]>O1CCOCC1>[C:2]1([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCNc1ccccc1
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(NCCCCNc2ccccc2)cc1
Temperature: 80 °C
Yield: 89.9 %

Procedure:
Following general procedure F, a mixture of chlorobenzene (51 μL, 0.5 mmol), N1-phenylbutane-1,4-diamine (98 mg, 0.6 mmol), NaOt-Bu (97 mg, 1.0 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and dioxane (0.5 mL) was heated to 80° C. for 2 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 0-75% EtOAc/hexanes) to provide the title compound as a clear oil (108 mg, 91%). 1H NMR (300 MHz, CDCl3) δ: 7.28 (t, J=7.0 Hz, 4H), 6.80 (t, J=7.0 Hz, 2H), 6.68 (d, J=7.0 Hz, 4H), 3.68 (s, 2H), 3.22 (m, 4H), 1.78 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ: 148.6, 129.6, 117.6, 113.1, 44.0, 27.4 ppm. IR (neat, cm−1): 3407, 3050, 2934, 2861, 1603, 1507, 1477, 1321, 1257, 1179, 749, 693. Anal. Calcd. for C16H20N2: C, 79.96; H, 8.39. Found: C, 80.20; H, 8.48.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10](Br)=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(-c2nc(N)nc(SC)c2C#N)o1
Temperature: 100 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 492 mg (1.58 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 15 ml dioxane under argon at room temperature were added 0.59 ml (1.74 mmol) (I-ethoxyvinyl)tributylstannane and 111 mg (0.16 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (1/2 ethyl acetate/hexane then 1/1 ethyl acetate/hexane then ethyl acetate) followed by trituration in ether afforded 304 mg (64%) 2-amino-4-[5-(1-ethoxy-vinyl)-furan-2-yl]-6-methylsulfanyl-pyrimidine-5-carbonitrile as an off-white crystalline solid. EI-MS m/e (%): 302 (M+, 88), 273 ([M—C2H5]+, 100), 243 (43), 231 (52).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](I)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:13][N:14](C)C=O>C(OCC)(=O)C>[NH2:9][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ncc(C(F)(F)F)cc1I
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4═CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]([NH2:20])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:18][NH2:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: NC(=O)[C@H]1CCCN1C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@H]1CCCN1C1CCCCC1
Yield: 96 %

Procedure:
Lithium aluminium hydride (7.3 ml, 1M in tetrahydrofuran, 7.3 mmol) was added dropwise to a solution of (2R)-1-cyclohexyl-2-pyrrolidinecarboxamide (preparation 147) (950 mg, 4.85 mmol) in tetrahydrofuran (15 ml) and once addition was complete, the reaction was heated under reflux for 20 hrs. The cooled mixture was carefully quenched with water, and extracted with ethyl acetate. The combined organic extracts were then dried over MgSO4 and evaporated under reduced pressure. The residue was suspended in dichloromethane, filtered through Whatman® fibre and the filtrate evaporated under reduced pressure to give the desired product as an oil (849 mg, 96%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.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]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:13](=[O:25])[C:14]3[S:20][C:19]4[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=4[C:15]=3[CH2:16][CH2:17]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 57.3 %

Procedure:
A 25 mL sealed tube was charged with 212b (990 mg, 2 mmol), 5-bromo-1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)pyridine-2(1H)-one 198e (500 mg, 1.3 mmol), CH3COONa (220 mg, 2.6 mmol), K3PO4 (700 mg, 2.6 mmol), and PdCl2(dppf) (110 mg, 0.13 mmol) suspended in CH3CN (25 mL) and water (1 mL). The mixture was heated at 110° C. for 2 hours. It was evaporated and the residue was purified by silical-gel column eluting with 20:1 methylene chloride/methanol to give 212c as a brown solid (500 mg, 56%). LCMS: [M+H]+ 670
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25]C)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O1CCCC1.[OH-].[Na+].Cl>O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([OH:25])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate from Step 2 (1.0 g, 2.66 mmol) was added to tetrahydrofuran (20 mL). Aqueous sodium hydroxide (2.5 N, 2.7 mL) and water (2.5 mL) were added, and the suspension was heated to reflux and held for 16 hours. The solids dissolved during this time. The reaction was cooled to room temperature, and hydrochloric acid solution (1 N, 11 mL) was added. The aqueous suspension was extracted with methylene chloride (2×20 mL). The combined organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 30 mL of dichloromethane yielded, upon filtration and drying, 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (0.90 g (94%)) as a white solid: mp 126-128° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[C:6]([Br:8])[CH:7]=1.[CH2:11]([N:14]([CH3:16])[CH3:15])[C:12]#[CH:13]>C(NCC)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Cu](I)I.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>[Br:8][C:6]1[CH:7]=[C:2]([C:13]#[C:12][CH2:11][N:14]([CH3:16])[CH3:15])[C:3]([CH3:10])=[N:4][C:5]=1[CH3:9]
Reactant: C#CCN(C)C
Reactant: Cc1nc(C)c(Br)cc1Br
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: Cc1nc(C)c(C#CCN(C)C)cc1Br
Temperature: 50 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
To a mixture of 3,5-dibromo-2,6-dimethylpyridine (605 mg, 2.54 mmol), copper iodide (22 mg, 0.11 mmol) and bis(triphenylphosphine)palladium(II)chloride (41 mg, 0.058 mmol) in diethylamine (3.0 mL) was added propargyl(dimethylamine) (0.27 mL, 2.50 mmol). The reaction mixture was allowed to stir for 15 h at 50° C. and was then allowed to cool to rt. The resulting mixture was diluted with EtOAc (30 mL) and 1M aqueous Na2CO3 (20 mL). After stirring for 30 min, the organic solution was separated and the aqueous solution was extracted with EtOAc (2×15 mL). The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(5-bromo-2,6-dimethylpyridin-3-yl)-N,N-dimethylprop-2-yn-1-amine (313 mg, 51%) as a dark oil. LCMS (AA): Rt=1.47 min, m/z=267.1 (M−H), 269.1 (M+H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[OH:26])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7].Cl>O.C(O)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@@H:25]([OH:26])[CH2:24][NH:23][CH2:22][CH2:21][NH:20][C:16]2[CH:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.36 %

Procedure:
A solution of 10% lithium hydroxide monohydrate in water (2 mL) was added to a solution of (R)-3′-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-ethylamino}-biphenyl-3-carboxylic acid methyl ester (50 mg, 0.12 mmol, 1.00 equiv) in ethanol (4 mL). The solution was stirred at ambient temperature for about 16 hours, and then the pH value of the solution was adjusted to 7-8 with concentrated hydrogen chloride. After concentrating the solution in vacuo, the resulting crude residue was purified by prep-HPLC to give the title product of as a white solid (20 mg; yield=41.36%). LC-MS: m/z=411 (MH)+. Retention time: 1.69 minute. [α]20.4D −20° (c=0.075, MeOH). [a]=−20° (c=0.075 g/100 ml in methanol, T=20.4). 1H NMR (300 MHz, CD3OD) δ: 8.22 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.29-7.38 (m, 4H), 7.20 (t, J=8.1 Hz, 1H), 6.97 (m, 2H), 6.68 (d, J=1.5 Hz, 1H), 5.00 (m, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.23-3.33 (m, 3H), 3.12 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][OH:13])[NH:9][C:8]=2[CH:14]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][OH:13])[NH:9][C:8]=2[CH:14]=1
Reactant: O=[N+]([O-])c1ccc2nc(CO)[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2nc(CO)[nH]c2c1
Reaction time: 3 h

Procedure:
(6-Nitro-1H-benzoimidazol-2-yl)-methanol (1.00 g, 5.18 mmol) was dissolved in methanol (50.0 mL) and 3.00 M hydrogen chloride in methanol (8.63 mL, 25.9 mmol). 10% Palladium on Carbon (50% wet) (55.1 mg, 0.0259 mmol) was added and the reaction was hydrogenated at 40 psi. for 3 hours. The reaction was then filtered through celite to remove the catalyst and then concentrated under reduced pressure to obtain (6-Amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride as a brown foam (1.13 g, 92%). Product is used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C[Si]([N:13]=[C:14]=[O:15])(C)C>C(O)(C)C>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:14]([NH2:13])=[O:15])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: CC1CN(C(N)=O)CC(C)O1
Reaction time: 8 h

Procedure:
To a stirred solution of 2,6-dimethylmorpholine (mixture of cis- and trans-isomers, 1.7 g, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give a mixture of cis- and trans-2,6-dimethyl-morpholine-4-carboxylic acid amide (2.7 g, quant.) as a solid; m/z (ES+) 158 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]3)[CH2:20][CH2:19]2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-((3-hydroxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (25 mg, 0.053 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (27 mg, 0.10 mmol) to afford the desired product (17 mg, 60%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.11 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.7, 2.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J=11.8, 1H), 4.46-4.38 (m, 1H), 4.18-4.10 (m, 1H), 3.08-3.01 (m, 2H), 2.93-2.78 (m, 3H), 2.70-2.64 (m, 2H), 2.331 (d, J=12.9 Hz, 2H), 2.23-2.12 (m, 1H), 2.01 (t, J=13.6 Hz, 2H), 1.87-1.80 (m, 1H), 1.75-1.71 (m, 1H), 1.56 (q, J=12.4 Hz, 2H), 1.27-1.05 (m, 6H). ESI MS m/z 538 [C30H33ClFN3O3+H]+; HPLC>99% (AUC), tR=10.78 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=2)[N:3]=1.[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=2)[CH2:22][CH2:21]1>C(O)C>[CH:20]1([C:23]2[NH:27][N:26]=[C:25]([NH:28][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=4)[N:3]=3)[CH:24]=2)[CH2:22][CH2:21]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Cl)n2)cc1
Solvent: CCO
Product: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 85 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
A mixture of 2-(4-(4-chloro-5-nitropyrimidin-2-yl)phenyl)acetonitrile (55 mg, 0.2 mmol, 1 equiv.) and 5-cyclopropyl-1H-pyrazol-3-amine (37 mg, 0.3 mmol, 1.5 equiv.) in ethanol (2 ml) was stirred at 85° C. for 15 h. Ethanol was remove under reduce pressure. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1) to afford 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidin-2-yl)phenyl)acetonitrile (45 mg, 62%) as solid. The compound was determination by LC-MS (LC-MS (m/z)=362.1 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cccc(F)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cccc(F)c1Cl

Procedure:
2-Chloro-3-fluorobenzaldehyde (2.5 g) and (R)-(+)-2-methyl-2-propanesulfinamide were dissolved in dichloromethane (50 ml), and then titanium(IV) isopropoxide (23.6 ml) was added. The mixture was heated for three hours under reflux, then poured onto ice (150 g) and stirred vigorously for ten minutes. The mixture was filtered through kieselguhr and the filtrate was extracted with dichloromethane (3×50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The product (4 g) was used further without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[CH:15]=3)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:30]1([C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH:16]5[CH2:21][CH2:20][CH2:19][CH2:18][O:17]5)[CH:15]=4)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(Cl)ncnc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C3CCCCO3)c2)c2c(N3CCOCC3)ncnc21

Procedure:
A solution of 4-chloro-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C18) (3.3 g, 7.6 mmol), morpholine (0.99 g, 11 mmol) and N,N-diisopropylethylamine (6 mL, 34 mmol) in n-butanol (15 mL) was irradiated in a microwave synthesizer at 100° C. for 30 minutes. After removal of solvents in vacuo, the residue was purified by silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) to provide the product as a brown oil. Yield: 2.6 g, 5.4 mmol, 71%. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.17 (s, 1H), 5.62 (s, 2H), 5.44 (dd, J=6.5, 6.0 Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.62-3.67 (m, 4H), 3.58 (dd, J=8.5, 8.0 Hz, 2H), 3.33-3.39 (m, 4H), 2.06-2.19 (m, 3H), 1.62-1.79 (m, 3H), 0.93 (dd, J=8.5, 7.5 Hz, 2H), −0.04 (s, 9H).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C[N:8]2[C:12]3[CH:13]=[C:14]([F:30])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH:27]4[CH2:29][CH2:28]4)[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:31][CH:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]2)=CC=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[CH:27]1([N:23]2[C:24]3[C:20](=[CH:19][C:18]([C:15]4[C:14]([F:30])=[CH:13][C:12]5[NH:8][C:9]([O:31][CH:32]6[CH2:33][CH2:34][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:37]6)=[N:10][C:11]=5[C:16]=4[F:17])=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1

Procedure:
To a solution of ethyl 4-{[1-(biphenyl-4-ylmethyl)-5-(1-cyclopropyl-1H-indol-5-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexane-carboxylate (0.080 g, 0.124 mmol) and Pd(OH)2 (0.023 g, 0.032 mmol) in 1.65 mL of EtOAc and 0.83 mL of EtOH was added 1,4-cyclohexadiene (0.300 mL, 3.19 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, then filtered through a Celite™ pad, and washed with 100% EtOAc. The resulting filtrate was concentrated in vacuo. Purification of the resulting crude residue by preparative TLC (40% EtOAc/hexanes) afforded the title compound. LCMS: calculated for C27H27F2N3O3 479.52, observed m/e 480.1 (M+11)+ (Rt 2.58/4 min).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of ethyl {4-[(butyl{6-[4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)methyl]-2-methylphenoxy}acetate (150 mg, 0.3 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×50 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a bright yellow solid (115 mg).