Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.P([CH:28]1[CH2:33][CH2:32]CCC1)(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:32]1([C:2]2[C:11]([O:12][CH3:13])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([CH3:14])=[N:9]3)=[CH:4][CH:3]=2)[CH2:33][CH2:28]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: COc1c(Br)ccc2ccc(C)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OB(O)C1CC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C2CC2)ccc2ccc(C)nc12
Temperature: 25 °C
Yield: 895.1 %

Procedure:
A solution of 7-bromo-8-methoxy-2-methylquinoline (1.00 g, 3.97 mmol), Pd(OAc)2 (0.045 g, 0.198 mmol), P(Cy)3 (0.122 g, 0.44 mmol) and cyclopropylboronic acid (0.68 g, 7.93 mmol) in toluene (4 mL) and water (0.4 mL) was stirred at 100° C. for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 7-cyclopropyl-8-methoxy-2-methylquinoline (0.84 g, 99%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=O)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2cc(OC)ccc2C1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCc2cc(OC)ccc2C1
Yield: 76.3 %

Procedure:
(RS)-6-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (2.0 g, 8.05 mmol) in MeOH (20 ml) and Pd/C (10%), (200 mg) was stirred vigorously under a hydrogen atmosphere for 3 hr at ambient temperature. The catalyst was removed and solvent evaporated to afford an oil, which was purified by chromatography over SiO2 (Merck 230-400 mesh) eluting with EtOAc-nHexane (1:9) to afford (RS)-6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester as a colourless oil (1.88 g, 6.14 mmol, 76%), MS ml/e=234.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C)=[CH:4][C:3]=1[F:12].[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)C>C(Cl)Cl>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(F)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 1,2-difluoro-4,5-dimethoxybenzene (5 g, 28.71 mmol, Aldrich) in methylene chloride (300 mL) cooled to 0° C. was added aluminum chloride (14.16 g, 106.2 mmol, Fluka) in several portions. At the end of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 12 hours. Water was added to quench the reaction. Diethyl ether (200 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (50 mL). The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 10% ethyl acetate in hexanes) yielded 4,5-difluoro-2-methoxy-phenol as dark oil (3.75 g, 82%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:8]=[C:7]([NH:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:6]=1)[CH2:2][CH:3]=C.O=[O+][O-].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O1CCCC1>[N:34]1([CH2:3][CH2:2][CH2:1][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:19])([F:18])[F:20])[N:8]=[C:7]([NH:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[CH:6]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: C=CCCc1cc(Nc2n[nH]c3ncccc23)nc(-c2ccccc2C(F)(F)F)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: FC(F)(F)c1ccccc1-c1nc(CCCN2CCOCC2)cc(Nc2n[nH]c3ncccc23)n1
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of [6-but-3-enyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine (0.10 g, 0.25 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) at −78° C. was bubbled through with ozone for 5 minutes. To this mixture was added morpholine (0.05 mL, 0.56 mmol) and sodium triacetoxyborohydride (0.39 g, 1.85 mmol). The reaction was stirred at room temperature for 24 hours when additional morpholine (0.10 mL, 1.28 mmol) and sodium triacetoxyborohydride (0.39 g, 1.85 mmol) were added then the stirring continued another 2 hours. The reaction was quenched with sodium bicarbonate and evaporated. Purification by flash chromatography (SiO2, eluted with 1:9 methanol:dichloromethane), followed by preparative HPLC provided the title compound as a bright yellow lyophilate (0.068 g, 38% yield). 484.3 (M+H). 1H-NMR (500 MHz, DMSO-d6) δ 13.2 (s, 1H), 10.7 (s, 1H), 9.60 (br s, 1H), 8.52 (m, 1H), 8.47 (d, 1H), 7.86 (d, 1H), 7.77 (m, 1H), 7.70 (m, 2H), 7.14 (m, 1H), 3.97 (br m, 2H), 3.61 (br m, 2H), 3.44 (br m, 2H), 3.18 (br m, 2H), 3.05 (br m, 2H), 2.78 (t, 2H), 2.08 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=1
Reactant: COC(=O)c1cnc(NCc2ccc(OC)cc2OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2cc(OC)c(C(=O)O)cn2)c(OC)c1
Reaction time: 15 h
Yield: 80.1 %

Procedure:
Methyl 6-[(2,4-dimethoxyphenyl)methylamino]-4-methoxypyridine-3-carboxylate (1.16 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). An aqueous potassium hydroxide solution (1 M, 7 mL) was added to the solution at room temperature. The reaction solution was stirred for 15 hours, and the organic solvent was then distilled off under reduced pressure. The obtained residue was diluted with water, and hydrochloric acid (1 M, 7.5 mL) was then added thereto. The resulting suspension was filtered, and the product collected by filtration was washed with water and dried under reduced pressure to obtain the title compound (0.890 g).
Reaction SMILES: I[C:2]1[C:3]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][C:23]1[N:28]=[C:27]([S:29][CH3:30])[N:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[N:24]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.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>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([NH:13][C:3]2[C:2]([C:25]3[N:24]=[C:23]([CH3:22])[N:28]=[C:27]([S:29][CH3:30])[N:26]=3)=[CH:7][N:6]=[C:5]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:4]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(Nc2nc(N3CCCC3)ncc2I)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 19.2 %

Procedure:
A glass microwave reaction vessel was charged with 5-iodo-N-(6-methoxypyridin-3-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (141 mg, 0.355 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (153 mg, 0.355 mmol), copper(I) iodide (14 mg, 0.071 mmol), cesium fluoride (108 mg, 0.710 mmol), tetrakis(triphenylphosphine)palladium(0) (41.0 mg, 0.035 mmol) and dioxane (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as brown oil. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (28 mg, 0.068 mmol, 19.22% yield). 1H NMR (300 MHz, CDCl3) δ 11.74 (s, 1H); 9.45 (s, 1H); 8.49 (s, 1H); 8.13 (dd, J=8.92, 2.34 Hz, 1H); 6.77 (d, J=8.77 Hz, 1H); 3.95 (s, 3H); 3.58-3.76 (m, 4H); 2.59 (s, 3H); 2.57 (s, 3H); 1.93-2.09 (m, 4H). m/z (ESI, +ve ion) 411.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C.O>[OH:59][CH2:58][C:57]([NH:56][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[CH:16][CH:17]=1)=[O:23])([CH3:61])[CH3:60]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (69.4 mg, 0.21 mmol) in DMF (1.1 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (74.1 mg, 0.23 mmol), N,N-diisopropyl ethyl amine (179 μL, 1.05 mmol) and 2-amino-2-methyl-1-propanol (20.6 mg, 0.23 mmol). The resulting reaction mixture was stirred for 30 min at room temperature and diluted with water. The mixture was then extracted with ethyl acetate and the combined organic layers washed with aqueous sodium carbonate (saturated) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 3:7) afforded the title compound (74 mg, 88%) which was obtained as an off white solid. MS: m/e=402.4 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([OH:11])[CH2:8][NH:7]1)=[O:5].[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]=[C:23]=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([NH:22][C:23]([N:7]2[CH2:8][C@H:9]([OH:11])[CH2:10][C@H:6]2[C:4]([O:3][CH3:2])=[O:5])=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)C1CC(O)CN1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C

Procedure:
The title compound was prepared from compound 56A (300 mg, 1.65 mmol) and isocyanate 23E (312 mg, 1.62 mmol) by procedures analogous to that described for Example 55A to afford a white foam (375.6 mg, 69%). HPLC: 1.68 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=12.92 min (98.9%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Reactant: OB(O)c1cccnc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C1CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), pyridine-3-boronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 414 as a white solid (29 mg, 43%). LCMS (Method K): RT 2.80 min [M+H]+ 415.06. 1H NMR (CDCl3 400 MHz): δ 8.74 (1H, s), 8.66 (1H, dd, J=4.86, 1.69 Hz), 8.17 (1H, s), 7.86 (1H, s), 7.70 (1H, dd, J=8.79, 4.66 Hz), 7.43 (1H, dd, J=7.83, 4.85 Hz), 7.13 (1H, dd, J=10.24, 8.78 Hz), 6.45-6.14 (1H, br m), 5.97 (1H, m), 5.36 (2H, s), 2.95 (1H, m), 1.70 (3H, d, J=6.73 Hz), 1.02-0.09 (4H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:16][C:5]([O:4][C:3]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=1[Cl:1])([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)Oc1ccc(Cl)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Yield: 82 %

Procedure:
37.5 parts of methyl 2-(2',4'-dichlorophenoxy)-propionate and 26.7 parts of N-bromosuccinimide in 300 parts of carbon tetrachloride are boiled under reflux, 0.1 part of azo-bis-isobutyronitrile being added every 45 minutes. The mixture is refluxed until the succinimide formed floats on the solvent. A total reaction time of 10 hours is required. The mixture is then cooled to 0° C. and filtered, and the filtrate is concentrated under reduced pressure. 36.9 parts (82% of theory) of methyl 2-bromo-2-(2',4'-dichlorophenoxy)-propionate, of nD22 =1.5395, are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1.O>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][C:7]=1[Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc([C@@H]2CC[C@H](O)C2)cn1
Solvent: CC#N
Solvent: O
Product: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate (35 mg, 0.092 mmol) in DCM (461 μl) was added HCl (922 μl, 3.69 mmol), the reaction mixture was stirred at room temperature overnight and concentrated to dryness yielding HCl salt. The crude product was used in next step reaction without purification. LCMS (m/z): 180.1 (MH+), 0.22 min. (+/−)-(1S,3R)-3-(5-aminopyrazin-2-yl)cyclopentanol (15 mg, 0.084 mmol) was dissolved in acetonitrile (2 mL), then NBS (16.39 mg, 0.092 mmol) was added, the reaction mixture was stirred at room temperature for 30 min, water was added, the reaction mixture was then extracted by EtOAc, the organic was dried and concentrated, the crude material was used in next step reaction. LCMS (m/z): 258.1/260.2 (MH+), 0.45 min. Following the above method, using (+/−)-N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate, (+/−)-(1R,3R)-3-(5-amino-6-bromopyrazin-2-yl)cyclopentanol was obtained. LCMS (m/z): 258.1/260.1 (MH+), 0.50 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=O.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH:12]1([O:11][C:9]2[CH:8]=[C:4]([CH:3]=[C:2]([F:1])[CH:10]=2)[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:21][CH:20]=2)=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(F)cc(OC2CCCCC2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(OC2CCCCC2)c1
Yield: 26.9 %

Procedure:
3-Fluoro-5-cyclohexyloxybenzoic acid (100 mg, 420 μmol), 4-amino-1-(2-morpholinoethoxy)naphthalene (103 mg, 378 μmol), HBTU (238 mg, 630 μmol), DIPEA (220 μl, 1.26 mmol), and DMF (1.5 ml) are stirred for 12 hours at room temperature. CH2Cl2 (2 ml) is added to the mixture, and it is then washed with H2O, NaHCO3 solution, and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to provide 3-(cyclohexyloxy)-5-fluoro-N-[4-(2-morpholin-4-ylethoxy)-1-naphthyl]benzamide as a brown solid (50 mg). Mp: 116-118° C.; 1H NMR(DMSO-d6) δ 10.29 (s, 1H), 8.21 (m, 1H), 7.87 (m, 1H), 7.57 (m, 2H), 7.52 (s, 1H), 7.42 (m, 2H), 7.07 (m, 2H), 4.51 (m, 1H), 4.31 (t, 2H), 3.61 (t, 4H), 2.89 (m, 2H), 2.62 (t, 4H), 1.93 (m, 2H), 1.72 (m, 2H), 1.46 (m, 6H); MS 493.32 (M+1).
Reaction SMILES: Br.Cl[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH2:18])[S:16][CH:17]=2)=[CH:9][CH:8]=1.Cl.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[F:35][C:21]([F:20])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[N:14]=[C:15]([NH2:18])[S:16][CH:17]=4)=[CH:9][CH:8]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)cs1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 2.61 g (7.5 mmol) of 4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole hydrobromide, 2.0 g (7.5 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 2.62 ml (15.0 mmol) of diisopropylethylamine, 1.59 g (15.0 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutylketone. The reaction was heated at reflux for 3.5 days, cooled, and the precipitate filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate and ethyl acetate as eluents. The product fractions were concentrated, taken up in methylene chloride/methanol, precipitated by addition of ethyl acetate saturated with hydrochloride, evaporated, and the residue triturated with ether/ethyl acetate to afford a white solid, m.p. 174°-179° C., 0.87 g (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1>CC(C)=O>[CH:1]1([N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: CN(C)CC1(c2ccc(OCC3CNC3)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)CC1(c2ccc(OCC3CN(C4CCCC4)C3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
Cyclopentyl bromide (0.17 ml, 1.54 mmol) and 5M aqueous sodium hydroxide (0.34 ml, 1.68 mmol) were added to a solution of 1-{4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-yl]-N,N-dimethylmethanamine (425 mg, 1.4 mmol) in acetone (9 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 2N hydrochloric acid to reach pH 1 and extracted with tert-butylmethyl ether (2×15 ml). The aqueous layer was then basified to pH14 with 4M sodium hydroxide (ca 40 ml) and extracted with dichloromethane (3×30 ml). These organic layers were combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1 by volume) to provide the title compound (55 mg, 11%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.28-1.73 (m, 8H), 1.83-1.93 (m, 2H), 1.96 (s, 6H), 2.05-2.13 (m, 2H), 2.40 (s, 2H), 2.71 (m, 1H), 2.90 (m, 1H), 3.00 (t, 2H), 3.39-3.58 (m, 4H), 3.72-3.78 (m, 2H), 4.05 (d, 2H), 6.87 (d, 2H), 7.21 (d, 2H). LRMS ESI+ m/z 373 [MH]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](O)=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:22]([C:17]1[CH:16]=[C:15]([C:14]2[O:25][C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:12][C:11]=3[N:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21])([O-:24])=[O:23]
Reactant: O=C(Nc1cc(-c2ccccc2)ccc1O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1Cl

Procedure:
Prepared by the method of Example 15c), from N-(5-phenyl-2-hydroxyphenyl)-3-nitro-4-chlorobenzamide (3.76 g, 10 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20 mmol) the subtitle compound was obtained (1.28 g, 40%). MS 351.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>ClCCl>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]=[CH:17][N:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=NC(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.15 g (50 mmol) of (diphenylmethyl)amine and 8.33 g (70 mmol of dimethylformamide dimethylacetal in 25 mL of dichloromethane was refluxed briefly and slowly distilled through a Vigreux column, distilling off all material that boiled at or below 90°. The residue was stripped in vacuo, poured into water, cooled, and the resulting solid filtered off. After drying, it was recrystallized from hexane to provide 8.3 g (70%) of N'-(diphenylmethyl)-N,N-dimethylmethanimidamide, mp 58-60.