Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH2:45][F:46])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>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.O>[F:46][CH2:45][CH2:44][O:43][C:40]1[N:41]=[CH:42][C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:38][CH:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: FCCOc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(OCCF)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 10.9 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.041 mmol), 5-bromo-2-(2-fluoroethoxy)pyridine (9.2 mg, 0.041 mmol), and 2 N aq Cs2CO3 (0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL) was added Pd(PPh3)2Cl2 (3 mg, 0.0041 mmol) under N2. The mixture was refluxed for 2 h under N2, treated with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give (S)-3-((S)-1-(4-(6-(2-fluoroethoxy)pyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (2.20 mg, 11%). LC-MS Method 2 tR=1.21 min, m/z=515, 493; 1H NMR (CD3OD): δ 0.95 (s, 3H), 1.26 (s, 3H), 1.54 (d, 3H), 2.15 (s, 2H), 2.21 (m, 1H), 2.46 (m, 2H), 3.02 (m, 1H), 4.50 (t, 1H), 4.57 (t, 1H), 4.66 (t, 1H), 4.79 (t, 1H), 5.57 (q, 1H), 6.88 (d, 1H), 7.02 (d, 2H), 7.31 (m, 7H), 7.85 (dd, 1H), 8.25 (d, 1H).
Reaction SMILES: C[Al](C)C.[N:5]1([S:10]([CH:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH3:14])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=[O:30])[NH:18][S:15]([CH:13]([S:10]([N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:11])=[O:12])[CH3:14])(=[O:17])=[O:16])[N:22]=1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 0 °C

Procedure:
9 ml (0.018 mol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) in 150 ml of dichloromethane. When the evolution of gas has ceased, 3.6 g (0.018 mol) of methyl 4-methoxy-6-methyl-1,3,5-triazin-2-ylcarbamate in 30 ml of dichloromethane are added dropwise, and the resulting solution is refluxed for 24 hours. It is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off, and the water phase is extracted twice with dichloromethane. The organic phase is dried and evaporated. After the crude product has been triturated with diethyl ether, 2.9 g (47% of theory) of 3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea of melting point 136°-137° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12].O>ClCCl>[CH2:3]([N:2]([CH3:1])[S:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N(C)Cc1ccccc1
Yield: 61 %

Procedure:
To a stirred solution of N-methyl benzylamine (7 ml, 54.2 mmol) in dichloromethane (10 ml) at 0-5° C. under an atmosphere of nitrogen was added dropwise a solution of methyl chlorosulfonylacetate (prepared by the method of M. J. Szymonifka and J. V. Heck, Tetrahedron Lett., 1989, 30, 22, 2869) (4.26 g, 24.7 mmol) in dichloromethane (5 ml), maintaining the temperature below 5° C. The yellow solution was then warmed to ambient temperature over a 2 hr period before water (30 ml) was added. The organic phase was partitioned and evaporated in vacuo to give a yellow oil. This was purified by flash column chromatography (diethyl ether:hexane 1:1 as eluant) to give the subtitle compound (3.9 g, 61%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1/[CH:11]=[CH:12]/[CH:13]=[C:14](/[N:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)\[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][C:42]=1[OH:49]>C(#N)C>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]2[N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][C:11]=2[C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:43][C:42]=1[OH:49]
Reactant: O=Cc1ccc(Cl)c(O)c1
Reactant: CCOC(=O)/C(=C\C=C\c1c(OC)cccc1OC)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(OC)cccc2OC)c(-c2ccc(Cl)c(O)c2)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
Reflux a solution of 7.54 g (14 mmol) of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate and 2.42 g (15.4 mmol) of 4-chloro-3-hydroxybenzaldehyde in 280 mL of anhydrous acetonitrile for 96 h. After cooling to RT, concentrate the reaction mixture under reduced pressure and purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/ethyl acetate (EtOAc) gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 2.4 g of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]([CH3:28])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:11][C:10]=2[O:29][CH3:30])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]([CH3:28])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:11][C:10]=2[O:29][CH3:30])=[N:6][CH:7]=1
Reactant: COc1cc(N(C)CCN2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-[2-(4-methylpiperazin-1-yl)ethyl]-5-nitrobenzene-1,4-diamine (0.182 g, 0.33 mmol), iron (0.110 g, 1.98 mmol) and NH4Cl (0.012 g, 0.23 mmol) in EtOH (10 mL) and water (3.33 mL) was heated at reflux for 1.5 h. The mixture was then cooled to r.t., filtered and concentrated in vacuo. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia provided a brown gum (162 mg) after concentration of appropriate fractions. Further purification by FCC, eluting with 2-7% 1M methanolic ammonia in CH2Cl2 gave the title compound (0.148 g, 86%) as a yellow gum; 1H NMR: (CDCl3) 2.28 (3H, s), 2.32-2.63 (10H, m), 2.70 (3H, s), 2.98 (2H, t), 3.84 (3H, s), 4.05 (2H, d), 6.71 (1H, s), 6.95 (1H, td), 7.38 (1H, ddd), 7.52 (1H, d), 7.88 (1H, s), 8.36 (1H, s), 8.57 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES+ MH+ 522.57.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1ccccn1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 35.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (125 mg, yield: 35.6%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][NH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.COCCOC>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:20]3[CH:19]=[N:18][NH:17][C:16]=3[CH3:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. After cooling to room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.208 g, 1.00 mmol), Cs2CO3 (0.489 g, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) were added. The mixture was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 6 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained yellow solid was triturated with EtOAc and collected by filtration to afford the title compound (52.7 mg, 38%) as a pale yellow solid:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:44])[NH:18][C:19](=[O:43])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17](=[O:44])[NH:18][C:19](=[O:43])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH2:29][NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CN(Cc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CNCc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1

Procedure:
A solution of the product of step (iii) (1.8 g) in trifluoroacetic acid (5 ml) and dichloromethane (30 ml) was stirred overnight at room temperature. Toluene was added and the mixture was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[N:18]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: O=C(O)c1cccc(C2=C(c3cc(Cl)ccc3O)CCC2)n1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccc(Cl)cc1)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)n1

Procedure:
6-[2-(5-Chloro-2-hydroxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid (97 mg, 0.30 mmol) was refluxed in 2-butanone (4 mL) with 4-chlorobenzyl bromide (140 mg, 0.70 mmol) and potassium carbonate (1.0 g) under nitrogen for five hours. The reaction mixture was then filtered through highflo, evaporated down to an oil and chromatographed on a Water's sep-pak (10 g) with ether/isohexane (15/85) to give the title compound. (160 mg, 92%). LC/MS [MH+] 556 Rt=5.5 min.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10]>[Cu]>[CH:1]1([O:11][C:9](=[O:10])[C:8]([F:13])([F:12])[F:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: C1=CCCCC1
Agent: [Cu]
Product: O=C(OC1CCCCC1)C(F)(F)F

Procedure:
Both experiments with copper metal deposited the white precipitate. During the course of the second experiment, solution samples were taken for analysis. Cyclohexene was found to be the major reaction product (ester/olefin=0.2) which slowly reacted with trifluoroacetic acid to form cyclohexyltrifluoroacetate. Thus, elimination of cyclohexene from a cyclohexyl-copper complex is the predominant reaction pathway under our conditions.
Reaction SMILES: [NH:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].CCOCC.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+]>[CH2:14]([O:21][C:22]([N:1]1[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 94 ml of 2-N NaOH was dissolved 25 g of L-thioproline, and 20 ml of ether was added to the solution under agitation and ice-cooling. To this solution under agitation were added dropwise 38 ml of benzyloxycarbonyl chloride and 70 ml of 4-N NaOH at the same time in 30 minutes. The mixture was stirred for 2 hours at room temperature, washed with 100 ml of ether and treated with 6-N HCl to adjust pH to 2. The mixture was extracted with 200 ml and 100 ml of ethyl acetate and the ethyl acetate phase was washed 50 ml of water, dried over MgSO4 and filtered. The filtrate was concentrated until dryness under reduced pressure whereby an oily substance was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[NH2:15].CCN(CC)CC.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.O.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.[Cu]I>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([NH:15][C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:2][CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Br)c(N)cc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC#C[Si](C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 86.1 %

Procedure:
To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et3N (27.9 mL, 200 mmol), Pd(PPh3)2Cl2 (2.11 g, 3 mmol), CuI (950 mg, 0.5 mmol) and trimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70° C. in a sealed pressure flask for 2.5 h., cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH4OH solution and water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-10% EtOAc/petroleum ether) to provide 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous liquid (25 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCc3ccc(Br)cc3C2)cn1
Temperature: 160 °C
Yield: 34.1 %

Procedure:
A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (0.30 g, 1.4 mmol), 5-bromopyridine-2-carbonitrile (0.28 g, 1.5 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in dimethyl sulfoxide (2.0 mL) was heated at 160° C. for 2 h. After cooled to r.t., the mixture was quenched with water (10 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with 30% ethyl acetate in hexanes to afford the desired product (0.15 g, yield: 34%). Analytic LCMS (M+H)+: m/z=314.2/316.2.
Reaction SMILES: IC1C2C(N(C)C)=NC=NC=2N(COCC[Si](C)(C)C)C=1.ClC1C2C(I)=CN(COCC[Si](C)(C)C)C=2N=CN=1.CN(C)C1C2C(C3C=C(C=CC=3)C#N)=CNC=2N=CN=1.[N:61]1([C:67]2[C:68]3[C:75]([B:76]4[O:80][C:79]([CH3:82])([CH3:81])[C:78]([CH3:84])([CH3:83])[O:77]4)=[CH:74][N:73]([CH2:85][O:86][CH2:87][CH2:88][Si:89]([CH3:92])([CH3:91])[CH3:90])[C:69]=3[N:70]=[CH:71][N:72]=2)[CH2:66]COC[CH2:62]1>>[CH3:66][N:61]([CH3:62])[C:67]1[C:68]2[C:75]([B:76]3[O:80][C:79]([CH3:81])([CH3:82])[C:78]([CH3:84])([CH3:83])[O:77]3)=[CH:74][N:73]([CH2:85][O:86][CH2:87][CH2:88][Si:89]([CH3:92])([CH3:91])[CH3:90])[C:69]=2[N:70]=[CH:71][N:72]=1
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)OC1(C)C
Agent: CN(C)c1ncnc2[nH]cc(-c3cccc(C#N)c3)c12
Agent: CN(C)c1ncnc2c1c(I)cn2COCC[Si](C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Product: CN(C)c1ncnc2c1c(B1OC(C)(C)C(C)(C)O1)cn2COCC[Si](C)(C)C

Procedure:
5-Iodo-N,N-dimethyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine [C3, prepared from 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) according to the method described for synthesis of 3-[4-(dimethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (5) in Example 5] was converted to the product according to the method described for synthesis of 4-(morpholin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P2) in Preparation P2. The product was obtained as a yellow solid. Yield: 342 mg, 0.817 mmol, 69%. LCMS m/z 419.3 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 (s, 1H), 5.56 (s, 2H), 3.49-3.57 (m, 2H), 3.25 (s, 6H), 1.36 (s, 12H), 0.86-0.94 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 158 °C

Procedure:
A mixture of 17.4 g of p-fluorobenzonitrile 31.0 g of ethyl p-hydroxyphenylacetate, 23.8 g of potassium carbonate and 175 ml of N,N-dimethylacetamide is heated at 158° C for 18 hours. The mixture is cooled and poured into 300 ml of cold sodium bicarbonate solution. The mixture is extracted with ether and the ether extracts washed with two 200 ml portions of 2N NaOH. The aqueous solutions are saturated with salt and extracted with ether. The alkaline aqueous layer is acidified with cold hydrochloric acid to give a solid which is filtered and washed with water to give tan crystals. Recrystallization by dissolving in 300 ml of methanol, adding 200 of water and chilling gives the product as yellow needles, mp 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([F:16])[CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1F

Procedure:
The title compound, MS: m/e=326.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-fluoro-4-methyl-benzene boronic acid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39].Cl>O.C1COCC1>[CH:36]([C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[OH:39])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1ccccc1O
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCCC=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a stirred suspension of pentyl triphenylphosphonium bromide (10.4 g, 25.2 mM) in freshly distilled THF (40 ml) was added LiN(SiMe3)2 (1M in THF, 50 ml). The reaction was stirred at ambient temperature for 1 hour. Salicylaldehyde (2.8 g, 22.9 mM) was added to the reaction mixture which was stirred at ambient temperature for 60 hours. The reaction was then treated with water, the pH adjusted with 1N aqueous HCl to pH7 and extracted twice with ethyl acetate. The organic layers were combined, dried over (MgSO4) and evaporated. The residue was purified by chromatography to give 2-(1-hexenyl)phenol, (3.57 g, 88%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](N(OC)C)=[O:27])=[CH:22][N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1.[CH2:43]([Mg]Br)[CH2:44][CH3:45].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:42])=[C:9]([CH2:11][O:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[O:27])[CH2:43][CH2:44][CH3:45])=[CH:22][N:21]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:40][CH3:41])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide (0.80 g) and tetrahydrofuran (30 mL) was added dropwise propylmagnesium bromide (2M tetrahydrofuran solution, 4.2 mL) at 0° C. and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (1E)-1-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-1-hexen-3-one as colorless crystals (0.32 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.