Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[N:13]=1.CN(C=O)C>CCOC(C)=O.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>[Br:14][C:12]1[N:13]=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:9]([NH2:15])=[N:10][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(Trimethylsilyl)acetylene (1.845 g, 2.655 mL, 18.78 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine 1 (5 g, 19.77 mmol) in DMF (25 mL) Triethylamine (10.00 g, 13.77 mL, 98.85 mmol), copper(I) iodide (451.7 mg, 2.372 mmol) and Pd(PPh3)4 (1.142 g, 0.9885 mmol) were then added and the resulting solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc and the combined organic layers washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with 15% EtOAc/Petroleum ether to give the product as a yellow solid (3.99 g, 75% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.30 (9H, s), 8.06 (1H, s); MS (ES+) 271.82
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].[C:5]([O-:8])(O)=[O:6].[Na+].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.O1CCOCC1.ClC(OCC1C=CC=CC=1)=O>[CH2:16]([O:8][C:5](=[O:6])[NH:4][CH2:3][C:2]#[N:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCN
Reactant: O=C([O-])O
Reactant: Cc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vigorously stirred solution of aminoacetonitrile (20 g; 0.216 mole), NaHCO3 (50 g; 0.595 mole) in water (450 ml) and dioxane (250 ml), 50% benzyl chloroformate in toluene (67.88 ml; 0.475 mole) was added at 0° C. After stirring at room temperature for 16 h, the reaction mixture was extracted with EtOAc. The EtOAc layer was washed with water and dried over anhydrous Na2SO4. Solvent was removed and the dark brown oil was purified by flash chromatography over silica gel with 30-50% EtOAc-PE 60-80° C. Yield, 33 g (80.3%); mp, 42-43° C.; MS (EI): 190 (M+), 145, 130, 117, 108, 91; analysis: C10H10N2O2 requires C, 63.15; H, 5.30; N, 14.73; found: C, 62.95; H, 5.05; N, 14.50%.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[N:21]=[C:20]([C:33]([NH:35][O:36][CH3:37])=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].C(O)(C(F)(F)F)=O.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])[N:21]=[C:20]([C:33]([NH:35][O:36][CH3:37])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC2COC(C)(C)O2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC(O)CO)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-methoxypyrimidine-4-carboxamide (Example 313; 0.60 g, 1.08 mmol) was dissolved in THF/water (4:1; 2.5 ml) and cooled to 0° C. TFA (0.1 ml) was added to the solution which was then slowly warmed to room temperature and stirred overnight. The mixture was neutralized with concentrated ammonium hydroxide and the THF was removed in vacuo. The mixture was diluted with water (4 ml), extracted with DCM, and the organic layers dried over magnesium sulfate. The mixture was concentrated in vacuo and crude product was purified by reverse phase chromatography eluting with acetonitrile/water (0.1% TFA) (33 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][C:24]=1[S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>C(#N)C>[Br:20][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:25]=1
Reactant: CS(=O)(=O)c1cc(CO)ccc1Cl
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(CBr)ccc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
(Step 1) Triphenylphosphine (2.38 g) was suspended in acetonitrile (30 ml), bromine (0.47 ml) was added, and the mixture was stirred for 30 min. [4-Chloro-3-(methylsulfonyl)phenyl]methanol (2.0 g) was added to the reaction mixture, and the mixture was stirred at 85° C. for 8 hr, treated with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:1) to give 4-(bromomethyl)-1-chloro-2-(methylsulfonyl)benzene (1.23 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([CH3:12])=[CH:7]2
Reactant: Cc1cc2c(N)ccc(F)c2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)ccc(F)c2cn1

Procedure:
Prepared from 8-fluoro-3-methylisoquinolin-5-amine (Description 76) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 378 (M+H)+.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(C1NC=CN=1)(C1NC=CN=1)=[S:13].C([O-])([O-])=O.[K+].[K+].CNC.[CH3:33][N:34]([CH:36]=O)[CH3:35]>COCCOC>[CH3:35][N:34]([CH3:33])[C:36]1[S:13][C:2]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=2[N:4]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CN(C)c1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-Fluoro-5-nitroaniline (1.7 g), thiocarbonyl diimidazole (1.9 g) and K2CO3 (2.9 g) were suspended in dry DME (20 mL) and stirred at RT for 12 h. 20 mL of DMF and dimethyl amine (40% in water, 8 mL) were added and the resulting mixture was heated at 65° C. for 3 h and 12 h at RT. Reaction was followed by LCMS and more dimethyl amine was added (5 mL) and heated again until reaction was almost completed. Solvent was evaporated and residue was dissolved in water. Mixture was extracted with EtOAc and filtered on silica pad. Solvent was removed to give N,N-dimethyl-5-nitrobenzo[d]thiazol-2-amine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.[Cl:24][C:25]1[O:35][C:28]2=[C:29]([NH2:34])[N:30]=[CH:31][C:32](I)=[C:27]2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[NH2:34][C:29]1[N:30]=[CH:31][C:32]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:22])[CH3:21])[CH2:18][CH2:19]3)[CH:13]=2)=[C:27]2[CH:26]=[C:25]([Cl:24])[O:35][C:28]=12
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Temperature: 100 °C
Yield: 86.6 %

Procedure:
A solution of 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (422 mg, 1.32 mmol) and 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (354 mg, 1.20 mmol) in 1,4-dioxane (8.06 mL) and H2O (2 mL) was charged with potassium carbonate (250 mg, 0.0018 mol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (9 mg, 0.01 mmol) under an atmosphere of nitrogen. The mixture was heated in a microwave at 100° C. for 40 min. The reaction mixture was dissolved in EtOAc and then washed with brine (2×). The aqueous layer was back-extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. The product was then purified by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) to afford 374 mg (86%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.05 (s, 1 H), 7.89 (s, 1 H), 7.83 (s, 1 H), 7.05 (s, 1 H), 4.67 (dd, J=13.52, 1.89 Hz, 1 H), 4.50 (tt, J=11.46, 4.20 Hz, 1 H), 4.08 (d, J=13.89 Hz, 1 H), 3.32-3.37 (m, 1 H), 2.79-2.91 (m, 1 H), 1.91-2.24 (m, 7 H). MS (ESI): 362.11 [M+H]+; HPLC tR=0.88 min (TOF: polar—3 min).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:17](=[N:16][CH:15]=[CH:14][CH:13]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (more polar isomer) (8 mg, 0.033 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C[Li].CCOCC.[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH2:18][S:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:24]=3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:31])[CH:10]=1.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CS(C)=O.O>[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH:18]([S:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:24]=3)[CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:31])[CH:10]=1
Reactant: Cc1cc(C)n2cc(CSc3nc(-c4ccccc4)c[nH]3)nc2n1
Reactant: ClCCN1CCOCC1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: Cc1cc(C)n2cc(C(CCN3CCOCC3)Sc3nc(-c4ccccc4)c[nH]3)nc2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of methyl lithium in ether (1.60 M, 0.205 mL, 0.328 mmol) was added dropwise to dimethyl sulfoxide (2.00 mL, 28.2 mmol) and the mixture left to stir for 40 minutes at room temperature. A solution of 5,7-Dimethyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-imidazo[1,2-a]pyrimidine (0.100 g, 0.298 mmol) and N-(2-chloroethyl)morpholine (0.0666 g, 0.358 mmol) in dimethyl sulfoxide was added dropwise to the generated dimsyl anion. The resulting mixture was stirred at 80° C. for 45 minutes. After cooling to room temperature, water was carefully added and the mixture was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo. Column chromatography of the crude product using ethyl acetate:methanol (95:5 v/v) gave the product as a yellow oil. It was dissolved in a minimum amount of methanol and ethereal hydrogen chloride was added dropwise to precipitate the hydrochloride salt of title compound as a yellow solid which was collected by filtration and washed with ether (71 mg, 49%). LC-MS: m/z=449.3 (MH+), tR=0.37 min, method C.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:30]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:31]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:69]([NH:71][C@H:72]([C:76](O)=[O:77])[C@@H:73]([CH3:75])[OH:74])=[O:70])[CH2:67][OH:68])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][C:52](=[O:54])[NH2:53])=[O:48])[CH2:45][OH:46])=[O:42])[CH2:32][S:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[NH:30]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:31]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:69]([NH:71][C@H:72]([C:76]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:77])[C@@H:73]([CH3:75])[OH:74])=[O:70])[CH2:67][OH:68])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][C:52](=[O:54])[NH2:53])=[O:48])[CH2:45][OH:46])=[O:42])[CH2:32][S:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CSCc1ccccc1)C(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.90 g (6 mmols) of H-Cys(Bzl)-Val-Leu-OH, 1.15TFA are dissolved in freshly distilled dimethylformamide, treated with 4.48 g (5.5 mmols) of BOC-Cys(Bzl)-Ser-Asn-Leu-Ser-Thr-OH and stirred at room temperature until all is dissolved. The solution is then cooled to 0°C, 1.26 g (11 mmols) of N-hydroxysuccinimide and 0.98 ml of triethylamine in 45 ml of dimethylformamide are added, followed by cooling to -22°C and the addition of 1.13 g (5.5 mmols) of dicyclohexylcarbodimide in 10 ml of dimethylformamide. The batch is stirred for 1 hour at -22°C, then at room temperature for 3 days, filtered to remove precipitated dicyclohexylurea, and evaporated to dryness. The residue is stirred twice with a mixture of 200 ml of ethyl acetate and 20 ml of 5% citric acid solution, then once with a mixture of 200 ml of ethyl acetate and 20 ml of 5% sodium bicabonate solution. The resulting product is filtered off and dried at 40°C in a high vacuum. Melting point: 218°-221°C; [α]D20 -28.5° (c = 2 in dimethylformamide); Rf8 = 0.43.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:38]2[CH:39]=[CH:40][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(C(C)(C)C)cc2)sc1C(=O)OCC
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester (1.0 g, 2.0 mmol), 4-tert-butylphenyl boronic acid (0.71 mg, 4.0 mmol), cesium carbonate (1.43 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0)(347 mg, 0.3 mmol) were suspended in 10 mL of 1,4-dioxane. The reaction was heated at reflux temperature overnight, cooled to room temperature and diluted with ethyl acetate. The organic mixture was successively washed with saturated sodium bicarbonate and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to an oil residue, which was then purified by column chromatography, eluting the title compound from silica gel with a gradient of (0-70%) ethyl acetate in hexanes to yield 1.11 g of a yellow oil. MS: (+) m/z 577.2 (M+Na+).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.[I+].[Cu+].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>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cnc(Cl)c(C#C[Si](C)(C)C)c1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
To a solution of 3-(1-BOC-2-(R)-azetidinylmethoxy)-6-chloro-5-bromopyridine (660 mg, 1.75 mmol) in toluene (20 mL) was added NEt3 (0.7 mL), copper (I) iodine (33 mg), tetrakis(triphenylphosphine)palladium (0) (201 mg) and (trimethylsilyl)acetylene (0.30 mL, 2.10 mmol). The reaction mixture was stirred and heated at 100° C. for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtoAc, 5:1 to 2:1) to afford an oil (430 mg, 62%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H), 4.10 (m, 1H), 4.30 (m,1H), 4.50 (m, 1H), 7.37 (d, 1H, J=3.0 Hz), 8.05 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)O[Si](C(C)(C)C)(C)C)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:32].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[OH-].[NH4+:43]>C(O)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:32]=[C:38]([C:37]3[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=3)[NH:43][C:13]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(Cl)cc3)[nH]c2-c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A solution of 4-pyridyl-t-butydimethylsilyloxymethyl 4-t-butylphenyl ketone from Step C (170 mg, 0.44 mmol), copper (II) acetate (161 mg, 0.89 mmol), ammonium acetate (342 mg, 4.44 mmol) and 4-chlorobenzaldehyde (78 mg, 0.56 mmol) in acetic acid (3 mL) was heated to 110° C. for 5 h. The reaction mixture was then cooled to 0° C. and ice (4 g), ethyl acetate (4 mL) and concentrated ammonium hydroxide solution (4 mL) were added. After stirring for 30 min, the phases were separated and the aqueous layer extracted with ethyl acetate (2 times). The combined organic phases were successively washed with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-3% methanol in methylene chloride to yield the title compound as a pale yellow solid 102 mg, 59% yield), mass spectrum (CI) m/e=388 (M+1)+.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:17]2[NH:21][CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[C:7]1([CH:17]2[N:21]([C:24](=[O:25])[CH2:23][Cl:22])[CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc2c(C3NCCO3)cccc2c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)N1CCOC1c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nineteen and nine tenths (19.9) ml. of a benzene solution containing 5 g. of 2-α-naphthyl oxazolidine was combined with 50 ml. of benzene and 2.8 g. of chloroacetyl chloride. To this was added 2.6 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred at room temperature for 30 minutes after addition was complete, washed with water, separated and dried over magnesium sulfate. The solvent was stripped under vacuum. There was obtained a yield of 6.7 g. of an oil, the title compound, ND30 =1.6030.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]3[CH2:20][CH2:19]3)[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([NH:10][C:11]2[N:16]=[C:15]([N:2]([CH3:3])[CH3:1])[CH:14]=[C:13]([CH:18]3[CH2:20][CH2:19]3)[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 50 °C

Procedure:
17.9 ml of 33% (100 mmol) absolute ethanolic dimethylamine solution are added dropwise to 9.8 g (40 mmol) of 2-phenylamino-4-chloro-6-cyclopropyl-pyrimidine in 20 ml of absolute ethanol at room temperature in the course of 10 minutes, while stirring, and the yellow suspension formed is heated at 50° C. for one hour and then refluxed for a further hour. After evaporation of the solvent, the residue is taken up in 200 ml of methylene chloride and the mixture is washed twice with 100 ml of water each time, dried over sodium sulfate, filtered and freed from the methylene chloride by evaporation. The 10.2 g of a yellow oil which remain are purified by column chromatography over silica gel using methylene chloride as the mobile phase. After evaporation of the methylene chloride, a pale yellow oil remains, which crystallizes after some hours. The pale yellow crystals melt at 90°-91° C. Yield: 8.9 g (35 mmol; 87.5% of theory).