Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[OH:6][C@H:7]([CH2:13][C:14](=[O:16])[O-:15])[CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10].N1C(C)=CC(C)=CC=1C.Cl[CH:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][P:42]([O-:44])[O-:43].I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[OH-:6].[C:14]([CH2:13][C@@H:7]([O:6][P:42]([OH:44])([O:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])=[O:43])[CH2:8][N+:9]([CH3:12])([CH3:10])[CH3:11])([OH:15])=[O:16]
Reactant: [O-]P([O-])OCCCCCCCCCCCCCC(Cl)Cl
Reactant: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCCCCCCCCCCOP(=O)(O)O[C@H](CC(=O)O)C[N+](C)(C)C
Product: [OH-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 16.4 gm of the tetrafluoroborate salt of L-carnitine and 26 gm of collidine in 263 ml of acetonitrile is added 29.4 gm of dichlorotetradecylphosphite. The reaction mixture is stirred at room temperature for 17 hours and then a solution of 21.1 gm of sodium metaperiodate in 48.7 ml of water is added. After stirring at room temperature for two hours, the reaction mixture is filtered through Celite and the filtrate is concentrated under vacuum. The residue is flash chromatographed on normal phase silica gel, initially with a 50/30/3 ratio of chloroform/methanol/concentrated ammonium hydroxide and then with a 50/30/10 ratio of the same solvent system to yield a product that is then flash chromatographed on LiChroprep RP-8 silica gel using gradients from water to acetonitrile and to methanol. The title compound is isolated as an amorphous solid, (m.p. ~190° C. [dec]; 31P NMR=0.324 ppm; [α]25 =-10.34 C=1.0 MeOH).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:15]([CH:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=1)=[O:2].C1C(=O)N([Br:30])C(=O)C1>CN(C=O)C.O>[Br:30][C:16]1[C:17]2[C:22]([C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: O=Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
9-(4-Formylphenyl)anthracene (3.3 g, 12 mmole) was suspended in anhydrous DMF (40 ml). To the resultant suspension, a solution (8 ml) of NBS (2.3 g, 13 mmole, 1.1 eq) in anhydrous DMF was added and the obtained mixture was stirred at the room temperature for 10 hours and left standing for one night. After the reaction mixture was diluted with water (50 ml), the solid was separated by filtration and washed with methanol and a yellow solid (3.9 g, 90%) was obtained.
Reaction SMILES: FC(F)(F)[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C1(CBr)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][CH:11]=2)[CH:7]=[CH:8]1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-trifluoromethylindole, R5X=cyclopropyl-methylbromide; NH2A=(2-amino-thiazole-5-ylsulfanyl)-acetic acid ethyl ester
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[O:24][C@@H:23]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[S:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:29]([O:28][P:26]([CH2:25][C@H:23]1[S:22][CH2:21][C@H:20]([CH2:19][OH:18])[O:24]1)([O:31][CH2:32][CH3:33])=[O:27])[CH3:30]
Reactant: CCOP(=O)(C[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@@H]1O[C@@H](CO)CS1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of cis and trans 5-(t-butyldiphenylsilyloxy methyl)-2-(diethyloxyphosphinoylmethyl)-1,3-oxathiolane (example 129) (15.68 g, 31.83 mmol) in THF (280 mL) was added tetrabutylammoniumfluoride (1 M solution in THF) (38.2 mL, 38.19 mmol, 1.2 eq.) at 0° C. The mixture was stirred at room temperature for 30 min. after which it was evaporated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate:MeOH (95:5 to 93:7) to give 7.39 g of the compound in a 86% yield.
Reaction SMILES: [CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1F)=[O:6])[CH:2]([CH3:4])[CH3:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC(=O)c1ccccc1F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(=O)c1ccccc1N1CCCCC1
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of isobutyl-(2-fluoro-phenyl)-ketone 13 (0.928 gm, 5 mmole), piperidine (0.645 gm, 7.82 mole) and potassium carbonate (1.08 gm, 7.82 mmole) in 4 ml of DMF was heated for 4 hrs at 120° C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and water (30 ml) was added to the reaction mixture and then extracted with ethyl acetate (1×15 ml, 2×7 ml). The combined organic layers were washed with a saturated ammonium chloride solution (2×15 ml) and subsequently dried over sodium sulphate. The solvent was removed under reduced pressure to obtain isobutyl-(2-piperidino-phenyl)-ketone 10 in 95% yield (GC showed 90% Purity). 1HNMR CDCl3, (spectrum 13): 0.92(d, 6H), 1.60(m, 6H), 2.07(m, 1H), 2.95(m, 6H), 7.05(m, 2H). 7.35(m, 2H). IR (spectrum 14) (Neat): 2841, 1657(C═O), 1570, 1435, 1345, 738
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([C@H:13]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[O:37](C(OC(C)(C)C)=O)[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=O>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([C@H:13]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:9]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CC[C@@H](c2ccc(Br)cc2)N1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)CC[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of the title compound from Step C (1.20 g, 2.61 mmol) and N,N-diisopropylethylamine (0.910 ml, 5.21 mmol) in CH2Cl2 (15 ml) was added BOC2O (1.21 ml, 5.21 mmol) and the mixture was stirred at RT for overnight. The mixture was diluted with ethyl acetate (200 mL), washed with aqueous sodium hydrogen carbonate (saturated, 2×100 mL), with brine (100 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane 0%-10% to afford title compound as a colorless solid. Yield is 96%. LC-MS: m/z (E/S) 562.1 (MH)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH:9][CH:10]=[C:11]([C:25]#[N:26])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=1[Cl:24])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:27]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[Cl:24])=[C:11]([C:25]#[N:26])[CH:10]=[N:9]2)=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(OCCCCl)c2)c(Cl)cc1Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCCCl)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
A suspension of 3-(3-chloropropoxy)-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (462 mg, 0.95 mmol) in 40 mL of acetonitrile was heated to reflux and phosphorous oxychloride (0.60 mL) was added dropwise, via syringe. The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was cooled to 0° C. and saturated aqueous sodium bicarbonate was added. The mixture was stirred for 10 minutes and the solid was collected by filtration, washed with water. The solid was suspended in hot ethyl acetate and methanol and then filtered to provide 200 mg of 7-(3-chloropropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.30 (m, 2H), 3.84 (t, J=6 Hz, 1H), 3.88 (s, 3H), 4.01 (s, 3H), 4.32 (t, J=6 Hz, 2H), 7.46 (s, 1H), 7.51 (s, 1H), 7.81 (s, 1H), 8.14 (s, 1H), 8.81 (s, 1H), 10.83 (br s, 1H), MS (ES) m/z 466.1, 468.1 (M+H)+.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH3:12])([CH3:11])[C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:6][C:7]([C:8]([CH3:9])=[C:2]([C:1]#[N:5])[C:3]#[N:4])([CH3:12])[CH3:11]
Reactant: N#CCC#N
Reactant: CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=C(C#N)C#N)C(C)(C)C
Yield: 68.4 %

Procedure:
A solution of 9.9 g of malononitrile, 26.25 g of 3,3-dimethyl-2-butanone, 1.45 g of ammonium acetate and 2.25 g of acetic acid dissolved in 100 ml of toluene was refluxed for about 16 hours with the aid of a Dean-Stark Trap. The reaction mixture was diluted with 120 ml of toluene and washed with 200 ml water. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was distilled under vacuum to afford 15.2 g of 2-(1,1-dimethylethyl)-1,1-dicyano-1-propene as an oil. Yield 68%.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)C>CCCCO>[N:2]1[NH:5][CH2:7][CH:8]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: CN(C)CC1CCCCC1=O
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: C1CCC2CNN=C2C1

Procedure:
Hydrazine hydrate (28.0 mL) was dissolved in n-BuOH (200 mL) and cooled in an ice bath. A solution of 2-dimethylaminomethyl-cyclohexanone (64.0 g) in n-BuOH (50 mL) was added dropwise, the mixture was slowly warmed and refluxed for 20 hours. The solvent was evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:7]=1.OS(O)(=O)=O.C[C:21](C)=[O:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH:21]=[O:22])[CH:7]=1
Reactant: COc1ccc(F)cc1CCCC=O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(F)cc1CCCCC=O
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 9 (0.46 g, 2.0 mmol) in acetone (20 mL) was added H2SO4 (5%, 2 mL) and the reaction was heated to reflux for 1.6 h. After the reaction was cooled to room temperature, most of the solvent was then removed in vacuo. A solution of NaHCO3 (sat. 40 mL) was added and the organics were extracted with EtOAc (3×40 mL) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The crude product obtained by removal of the solvent in vacuo was purified by flash column chromatography on silica (Rf=0.10, EtOAc/Hexane, 10:90, v:v) to give the product (0.20 g, 50%) as oil; 1H NMR (CDCl3, 500 MHz): δ 9.76 (s, 1 H), 6.88-6.82 (m, 2 H), 6.74 (dd, J=4.6, 8.6 Hz, 1 H), 3.79 (s, 3 H), 2.61 (t, J=7.3 Hz, 2 H), 2.45 (m, 2 H), 1.69-1.60 (m, 4 H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[CH:9][N:8]=1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][C:2]2[N:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[S:5][C:6]=2[C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:10]=[CH:9][N:8]=2)=[CH:34][CH:33]=1
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of N-{4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.292 g, 0.589 mmol) in tetrahydrofuran (4.1 mL) was added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 2.36 mL, 1.18 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0226 g, 0.0442 mmol) under argon. The solution was stirred at 60° C. for 2 hours. The reaction was incomplete by LCMS, so additional 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 2 mL, 1 mmole) was added, then the reaction was stirred at 60° C. for an additional 2 hours. The reaction was allowed to cool to room temperature then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.112 g, 35%). LCMS: (FA) ES+, 542. 1H NMR (400 MHz, d4-methanol) δ: 8.73-8.69 (m, 1H), 8.42-8.38 (m, 1H), 8.14 (s, 1H), 7.58-7.55 (m, 1H), 7.27-7.20 (m, 4H), 5.52 (s, 2H), 4.32 (s, 2H), 3.68-3.61 (m, 2H), 2.20 (s, 3H), 0.90-0.84 (m, 2H), 0.040 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12](O)[CH:11]([CH:20]([NH:22][CH3:23])[CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:20]([NH:22][CH3:23])[CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(C)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h

Procedure:
To a solution of 44 (480 mg, 1.37 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred for 2 h before being concentrated. The residue was subjected to chiral AD column chromatography (ethanol/MeOH/hexane/DEA=3:2:93:0.1) to give 47 as a single diastereomer. The absolute stereochemistry for the stereocenter in the side chain of 47 was not determined. A second stereoisomer was formed, but could not be isolated in pure form. 1H NMR (400 MHz, CDCl3)δ 7.32 (d, J=8.0 Hz, 1 H), 7.25 (d, J=2.4 Hz, 1 H), 7.19 (d, J=7.2 Hz, 1 H), 7.15-7.07 (m, 2 H), 6.94 (dd, J=2.4, 8.4 Hz, 1H), 6.82 (d, J=7.2 Hz, 1 H), 6.47 (s, 1 H), 4.01 (t, J=8.4 Hz, 1 H), 3.64(q, J=6.4 Hz, 1 H), 2.71 (dd, J=7.6, 16.8 Hz, 1 H), 2.48 (dd, J=8.0, 16.8 Hz, 1 H), 2.09 (broad, 2 H), 1.16 (d, J=8.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3)δ 144.95, 143.12, 136.21, 134.01, 132.87, 130.42, 130.21, 128.02, 127.60, 127.62, 127.44, 126.78, 121.12, 52.47, 43.21, 32.58, 20.98; ESI MS m/z 318.0.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccncc2)nc1Cc1ccccc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(-c3ccncc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 196 mg of 2-benzyl-3-bromo-6-(4-pyridyl)pyridine, 100 mg of 3-ethynyl-3-quinuclidinol, 70 mg of tetrakis(triphenylphosphine)palladium(0), 11 mg of cuprous iodide, 0.25 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 85° C. for one hour in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel column chromatography and eluted with hexane/ethyl acetate (1:1) and then with methanol/ethyl acetate (20:1). After removing the solvent, the residue was recrystallized from hexane/ethyl acetate, to give 178 mg of the target compound.
Reaction SMILES: Cl.[CH:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]COC)[CH2:5][CH2:4][CH2:3]1.CCOC(C)=O>CO>[CH:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:3][CH2:4][CH2:5]1
Reactant: COCOc1ccccc1C1CCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccccc1C1CCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
After concentrated hydrochloric acid (3.1 mL) was added to a solution of 1-cyclobutyl-2-(methoxymethoxy)benzene (1.43 g) in MeOH (29 mL) at room temperature, the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, a standard buffer solution of pH 6.86 was added thereto, and EtOAc was added. Extraction was performed on the mixture using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure, whereby 2-cyclobutylphenol (1.1 g) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].C(O[CH:39](OCC)[CH2:40][NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)C>C1COCC1.C(OCC)(=O)C>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([N:1]4[CH:39]=[CH:40][N:41]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:24]4=[O:25])=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: CCOC(CNc1ccccc1)OCC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(-n3ccn(-c4ccccc4)c3=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 4-(2-(4-amino-phenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.200 g, 0.682 mmol) in THF (3 mL) under nitrogen was added 4-nitrophenyl chloroformate (0.138 mg, 0.682 mmol). The dark brown mixture was allowed to stir for 1 h, at which point N-(2,2-diethoxyethyl)benzenamine (0.285 mL, 1.36 mmol) was added. The reaction was heated to 80 deg. C. for 30 min. The reaction was cooled to ambient temperature, diluted with ethyl acetate, and washed with 3×saturated aqueous sodium bicarbonate, 2×1N NaOH, 1× water, and 1×brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in dichloromethane and filtered. The filtrate was concentrated to a brown oil, which was treated with 5 mL 1N HCl and was heated to 80 deg. C. in a sealed tube. After 1 h, the reaction was cooled to ambient temperature, filtered, and the solid was rinsed with small amounts of water and ethanol, and was dried in vacuo to give a tan solid. This material was further purified by reverse-phase HPLC using acetonitrile/water/TFA as eluent to give 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-phenyl-1H-imidazol-2 (3H)-one as an off-white solid. MS m/z=437 [M+1]+. Calc'd for C25H20N6O2: 436.47.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:10]=1/[CH:11]=[CH:12]/[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16](Cl)=[N:17][C:18]=2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([P:29]([CH3:32])([CH3:31])=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[CH3:8][C:9]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:10]=1/[CH:11]=[CH:12]/[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[N:17][C:18]=2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([P:29]([CH3:32])([CH3:31])=[O:30])=[CH:25][CH:24]=1
Reactant: c1c[nH]cn1
Reactant: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(-n3ccnc3)nc21
Temperature: 25 °C

Procedure:
Imidazole (0.16 g, 2.36 mmol) was dissolved in DMF (1.0 mL) in a CEM 10 mL microwave tube and to this was added NaH (0.09 g, 60% dispersion in mineral oil). The content was stirred at room temperature until no more bubbling was observed (˜10 min). Then (E)-9-(2,6-dimethylstyryl)-2-chloro-N-(4-(dimethylphosphoryl)phenyl)-9H-purin-6-amine (0.12 g, 0.236 mmol) was added. The reaction was heated with microwave (120° C., 10 min). Solvent was removed on rotavapor and the residue was partitioned between EtOAc/water, and the organic layer was separated and dried Na2SO4. The product was purified on ISCO combiFlash (12 g silica gel column, 5% MeOH/DCM): MS [M+H]+ 484.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Br:11]N1C(=O)CCC1=O.O.BrC1C=CC(C(C)C)=CC=1O>C(=S)=S>[Br:11][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)c1ccc(Br)c(O)c1
Solvent: O
Solvent: S=C=S
Product: CC(C)c1cccc(O)c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of 3-isopropylphenol (10.0 g, 73.4 mmol) in carbon disulfide (200 mL) was slowly added N-bromosuccinimide (13.1 g, 73.4 mmol) with ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was stirred at room temperature for 1 hour, and then water was added thereto, which was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85) to obtain a mixture of 2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol (3:1) 11.0 g (yield 70%).
Reaction SMILES: C1O[C:3]([CH2:10][C:11]([N:13]([CH:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)[CH3:14])=[O:12])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:37](=O)([O-])[O-:38].[K+].[K+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48](=[O:51])[CH2:49][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:15]([N:13]([C:11](=[O:12])[CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:38][CH:37]=2)[CH3:14])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:24])[CH3:25])[CH2:18]2)[CH:31]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C(=O)Cc1occ2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 18 h

Procedure:
To a solution of Example 25 (2.195 g, 4.32 mmol) in DMF (40 mL) was added powdered potassium carbonate (1.21 g, 8.77 mmol) followed by t-butylbromoacetate (0.85 mmol, 5.26 mmol). After stirring for 18 hours, the solution was diluted with water (100 mL) and extracted with ethyl acetate (4×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in ethyl acetate:heptane (6:4) gave the product as an oil. Yield=1.209 g, 45%.