Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: Cc1ccc(B(O)O)cc1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(C(C)N=[N+]=[N-])nc3scc(C)n3c2=O)cc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.080 g, 0.25 mmol) and (4-methylphenyl)boronic acid (0.042 g, 0.31 mmol) in 1,4-dioxane (2 mL) was added 1N solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.011 g, 0.015 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, concentrated and then purified on silica gel (0-25% ethyl acetate/hexane) to give the desired product (50 mg). LCMS calculated for C16H16N5OS (M+H)+: m/z=326.1. Found: 326.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.[CH2:26]([O:28][C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33](B(O)O)[CH:34]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:33]2[CH:34]=[C:29]([O:28][CH2:26][CH3:27])[CH:30]=[CH:31][C:32]=2[F:38])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: CCOc1ccc(F)c(B(O)O)c1
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: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)c(-c2ccc(C(=O)OC)cc2C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 21 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(trifluoromethylsulfonyloxy)benzoate T6.9 (0.400 g, 1.1 mmol) in DMF (4.00 mL) at 23° C. was added 5-ethoxy-2-fluorophenylboronic acid (0.29 g, 1.6 mmol, commercially available from Aldrich), potassium carbonate (0.44 g, 3.2 mmol), and then tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol). The mixture was heated to 90° C. and stirred for 21 hours. The mixture was then cooled to room temperature, diluted with brine, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T16.1 as a colorless oil (0.350 g, 90% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][C:23](O)=[O:24]>O>[OH:24][CH2:23][CH2:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:13][CH:14]=2)[NH:18][CH:17]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
LiAlH4 (1.99 g, 52.3 mmol) was placed in abs. THF (60 ml), under argon, and (5-hydroxy-1H-indol-3-yl)-acetic acid (5.00 g, 26.2 mmol) in abs. THF (100 ml) was added in the course of 30 min. The mixture was boiled for 3 h under reflux. For working up, THF (10 ml) and H2O (4 ml) were added to the mixture, while cooling with ice, and stirring was carried out for 30 min. The mixture was filtered over Celite and rinsed with dichloromethane (150 ml), and the filtrate was concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=[O:12])[S:10][C:4]=2[CH2:3]1.[Li+].[ClH:15]>C(O)C>[ClH:15].[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:4]=2[CH2:3]1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (3.00 g) was added 1N HCl in ethanol (36 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and were washed with ethanol (9 mL). The wet crystal was dried at room temperature under reduced pressure, to thereby give 2.76 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.[O:12]([C:14]#[N:15])[Na]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1)[C:14]([NH2:15])=[O:12]
Reactant: CNc1ccc2c(c1)OCO2
Reactant: N#CO[Na]
Product: CN(C(N)=O)c1ccc2c(c1)OCO2
Yield: 56 %

Procedure:
The title compound was prepared from N-methyl-3,4-(methylenedioxy)aniline and NaOCN by the procedure described in example 1 in 56% yield. 1H NMR (CDCl3): 6.75-6.64 (m, 3H), 6.02 (s, 2H), 4.42 (br s, 2H), 3.21(s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15]OS(C)(=O)=O)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:21]#[N:22].[K+]>CS(C)=O.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:21]#[N:22])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 77.2 %

Procedure:
To 4-methanesulfonyloxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.440 g, 1.43 mmol) dissolved in DMSO (3 mL) is added potassium cyanide (0.373 g, 5.73 mmol). The mixture is heated to 130° C. for 18 hours. The reaction mixture is cooled and diluted with EtOAc and water. The organic layer is concentrated, taken up in MeOH and concentrated again to give the title compound as a brown oil (263 mg, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22]>CN(C)C=O.O>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:22]
Reactant: Nc1ccncc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNc1ccncc1)OCC
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 13.5 %

Procedure:
A solution of 4-aminopyridine (23.2 g.) in a mixture of dried hexamethylphosphoric triamide (45 g.) and dried dimethylformamide (80 ml) was dropwise added over 20 minutes with stirring and ice-cooling to a suspension of 65.5% sodium hydride (10 g.) in dried dimethylformamide (20 ml.). After dried dimethylformamide (20 ml.) was further added thereto, the mixture was stirred for 1 hour under ice-cooling, for 20 minutes at ambient temperature and for 40 minutes at 50° C. A solution of bromoacetaldehyde diethyl acetal (54 g.) in dried dimethylformamide (20 ml.) was dropwise added thereto over 5 minutes at 50° C. The resulting mixture was stirred for 15 hours at 80° C and for 3 hours at 100° C. After cooling, water was added to the reaction mixture and the resulting mixture was concentrated under reduced pressure to remove dimethylformamide. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was in turn washed 3 times with water and once with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on alumina (300 g.) using a mixture of ethyl acetate and hexane (1 : 1) as a developing solvent to give oil of 4-pyridylaminoacetaldehyde diethyl acetal (7.0 g.).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (1.32 mmol) and tert-butyl isocyanate (1.32 mmol) using the procedure described for compound (10) (474 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:9]([C:10]#[N:11])([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:20]
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C(F)(F)F)cc1

Procedure:
Prepare by the method of example 1.1.2 using 4-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].[CH:13](OCC)=[O:14]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][CH:13]=[O:14]
Reactant: CCOC=O
Reactant: NCC1COc2ccccc2O1
Product: O=CNCC1COc2ccccc2O1

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 mL), refluxed for 30 min and evaporated in vacuo to yield N-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-formamide as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>COCCOC.O.[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>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C(F)(F)F)cc1
Yield: 56.9 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-(trifluoromethyl)phenylboronic acid (0.095 g; 0.5 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.061 g (57%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3OCC[O:18][C:11]=3C=2)[C:5]([F:19])=[CH:4][N:3]=1.ClC1N=C(Cl)C(F)=CN=1.C(N)C1OC=CC=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:14]2[O:18][CH:11]=[CH:12][CH:13]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Fc1cnc(Cl)nc1Cl
Agent: NCc1ccco1
Product: Fc1cnc(Cl)nc1NCc1ccco1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield 2-chloro-5-fluoro-N4-(furfuryl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.91 (d, 1H, J=1.8 Hz), 7.39 (d, 1H, J=1.2 Hz), 6.35 (m, 2H), 5.50 (bs, 1H), 4.69 (d, 2H, J=5.1 Hz); 19F NMR (CDCl3): −45163; LCMS: ret. time: 24.52 min.; purity: 97%; MS (m/e): 228 (M+).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OCCC)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].O>C(O)COCCO>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(NC(=O)OCCC)cc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc(-c2ccc(N)cc2)nc1
Temperature: 170 °C
Yield: 44.3 %

Procedure:
A solution of 2.24 g of propyl p-(5-pentyl-2-pyridyl)phenylcarbamate in 186 ml of diethylene glycol was treated with 26 ml of potassium hydroxide and 47 ml of water and heated at 170° C. under nitrogen. After 1.75 hours the reaction mixture was cooled, poured into 250 ml of water and extracted with methylene chloride. The organic phase was dried over sodium sulphate, filtered and freed from solvent on a rotary evaporator under a vacuum. Purification of the residue (1.39 g) by chromatography on 60 g of silica gel with 1.5 l of methylene chloride and 0.5 l of methylene chloride/ethyl acetate (vol. 4:1) and subsequent recrystallization from methylene chloride/hexane gave 0.731 g of p-(5-pentyl-2-pyridyl)aniline as yellowish crystals; m.p. 60.3°-61.3° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC2C=CC=CC=2)[CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=1)[CH2:6][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(C(F)(F)F)cc1)C(OC(=O)C(F)(F)F)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1cccc(O)c1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
The 3-(3-benzyloxy-phenyl)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (9.03 g, 15.8 mmol) was combined with 10% Pd/C (9.0 g) in ethyl acetate (200 mL). The mixture was purged with N2 then H2 and then stirred at room temperature under a H2 balloon for approximately 48 h. The reaction mixture was filtered through hyflo to remove the catalyst and the resultant filtrate dried (MgSO4). The solvent was removed in vacuo to give crude product that was purified by flash chromatography using 3:1 hexanes:acetone to afford 1.96 g (32%) 3-(3-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester. The racemic phenol was purified by preparative chiral HPLC (Chiralcel OD, 5×37 cm, 95:5 heptane:IPA mobile phase, 150 ml/min, 285 nm, GK8-A015150-031). Rf=0.32 (1:1 hexanes:acetone). 1 NMR. MS (ES−) Calc'd for C19H18O4F3 (M−1) 367. Found m/z 367 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C1C=CC2C(C3C(O)=CC=C4C=3C=CC=C4)=C(O)C=CC=2C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:39][C@H:40]1[CH2:45][NH:44][CH2:43][C@@H:42]([CH3:46])[NH:41]1>CCOC(C)=O.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:44]2[CH2:43][C@H:42]([CH3:46])[NH:41][C@H:40]([CH3:39])[CH2:45]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.2 %

Procedure:
A microwave vial was charged with 1-bromo-4-iodobenzene (1.0 g, 3.5 mmol), CuI (0.135 g, 0.707 mmol), BINOL (0.202 g, 0.707 mmol), and K3PO4 (1.5 g. 7.1 mmol). The vial was capped and then evacuated and backfilled with Ar. Cis-2,6-dimethylpiperazine (0.605 g, 5.30 mmol) and DMF (4 mL) were then added. The resulting mixture was stirred at rt for 4 d. The mixture was diluted with EtOAc, filtered through a cake of Celite and the filtrate was concentrated to give the crude product. Crude product was purified by flash chromatography using MeOH/CH2Cl2 (2:98 to 15:85) to give the title compound as a red solid (567 mg, 59%). 1H NMR (400 MHz, MeOD) δ 7.33 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.63-3.60 (m, 2H), 3.18-3.07 (m, 2H), 2.40 (t, J=11.6 Hz, 2H), 1.23 (d, J=6.4 Hz, 6H); MS ESI 269.0 [M+H]+, calcd for [C12H17BrN2+H]+ 269.06.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][NH:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:10][CH:9]([CH3:8])[O:14][CH:13]([CH3:15])[CH2:12]1
Reactant: Clc1ncccn1
Reactant: CC1CNCC(C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CN(c2ncccn2)CC(C)O1
Yield: 76.5 %

Procedure:
In a 100 mL recovery flask, 2-chloropyrimidine (1 g, 8.73 mmol), 2,6-dimethyl morpholine (cis:trans mixture, 1.106 g, 9.60 mmol), N,N-diisopropyl-N-ethylamine (1.241 g, 9.60 mmol), and ethanol (17.46 mL) were added and refluxed for seven hours. Upon completion of the reaction, the solvent was distilled off, and saturated sodium bicarbonate was added thereto. The resulting mixture was extracted with ethyl acetate twice, and the organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→1:2) to give the title compound (1.29 g, 76%, cis:trans mixture).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Reactant: COc1ccc(B(O)O)cn1
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: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(OC)nc3)nc(OC)n2)cc1
Temperature: 85 °C
Yield: 100 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (600 mg, 2.04 mmol), 2-methoxy-5-pyridyl-boronic acid (469 mg, 3.06 mmol, prepared according to the procedure described in J. Org. Chem., 2002, 67, 7541), and Cs2CO3 (1.66 g, 5.11 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL), at room temperature, is degassed with argon gas for 5 minutes and treated with tetrakis(triphenylphosphine)palladium (0) (118 mg, 0.1 mmol). The mixture is heated at 85° C. for 5 hours, diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with a mixture of EtOAc and heptane (1:1, v/v) affording [2-methoxy-6-(6-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [0.75 g, 100%, Example 35(o)] as an oil. LCMS: RT=2.74 minutes, MS: 367 (M+H). 1H NMR (300 MHz, CDCl3): □8.78 (1H, d, J=2.1 Hz), 8.21 (1H, dd, J=8.7, 2.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.88 (1H, dd, J=8.7, 2.4 Hz), 6.82 (2H, d, J=8.4 Hz), 6.3 (1H, s), 4.95 (1H, brs), 4.03 (3H, s), 4.02 (3H, s), 3.82 (3H, s), 3.72-3.63 (2H, m), 2.92 (2H, t, J=6.9 Hz). IC50=1.7 nM
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].CCOC(C)=O>CCN(CC)CC.[Cu]I.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>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 5-bromo-3-iodopyridin-2-amine (B-7-1) (20 g, 66.9 mmol) in Et3N (200 mL) was added CuI (1.27 g, 6.69 mmol), and the resulting mixture was degassed with N2 for 2 minutes. Then Pd(PPh3)2Cl2 (1.4 g, 20.1 mmol) was added and the mixture was degassed again. Then ethynyl-trimethyl-silane (7.2 g, 73.6 mmol) was added dropwise into the mixture at 0° C. The mixture was stirred at room temperature for 4 hours. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. The mixture was evaporated under reduced pressure to give crude mixture which was purified via a silica gel column eluted with petroleum ether/EtOAc (20:1) to afford 5-bromo-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (B-7-2) (10 g, 55.6%) as a white solid.
Reaction SMILES: [S:1]([O-:4])([OH:3])=[O:2].[Na+:5].[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCCCC)(=O)C=C.C(O)(=O)C(C)=C>O>[CH2:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([S:1]([O-:4])(=[O:3])=[O:2])=[CH:10][CH:9]=1.[Na+:5]
Reactant: O=S([O-])O
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 824.3 %

Procedure:
A 500-ml flask, the inner atmosphere of which was substituted with nitrogen, was charged with 0.07 g of a surface active agent (Emulgen 935 supplied by Kao-Atlas), 0.07 g of another surface active agent (Emulgen 920 supplied by Kao-Atlas), 0.3 g of sodium hydrogensulfite and 46.2 g of water, and the temperature was elevated to 40° C. with stirring in a nitrogen current. A liquid monomer mixture comprising 50 g of styrene, 50 g of n-butyl acrylate and 1 g of methacrylic acid, an aqueous solution of 4.9 g of sodium p-styrene-sulfonate having a purity of 82.0% (Spinomar NaSS supplied by Toyo Soda) in 45.1 g of water and an aqueous solution of a polymerization initiator formed by dissolving 0.5 g of ammonium persulfate in 49.5 g of water were added into the flask over a period of 3 hours and polymerization was carried out at 40° C. After completion of the addition, the polymerization temperature was maintained for 3 hours and the polymerization mixture was then cooled to room temperature.