Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].O>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:2][C:3]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Boc-Gly-ONp (50 g, 0.17 mol.) and proline (20.7 g, 0.175 mol.) were dissolved in 300 ml DMF. 20 ml TEA and 30 ml water were added while stirring the solution. The stirring was continued overnight and TLC analysis showed no more starting materials. The solvents were removed under reduced pressure and the resulting mixture was dissolved in 250 ml saturated Na2CO3. The aqueous solution was extracted by 3×100 ml ethyl acetate to remove p-nitrophenol. Then, after chilling to 0° C., the aqueous solution was acidified to about pH=3 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase by 3×150 ml ethyl acetate. The organic phase was combined and washed by saturated NaCl (brine) 3×20 ml, and dried using Na2SO4. TLC analysis showed there was still p-nitrophenol in the solution. The ethyl acetate was removed under reduced pressure and column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product Boc-Gly-Pro-OH (white solid, 41.2 g, 88%). TLC Rf=0.25 (CMA, 85:15:3). FAB-MS, observed (M+H)+ =273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ 12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 6.44 (s, NH-minor), 4.50 (dd, 0.25H, Pro-α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major), 3.47-3.33 (m, 2.5H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc-CH3)b.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21]>CN(C=O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:19][C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[N:8]=1)=[O:12])[CH3:15]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)Nc2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10 g 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester in 200 ml absolute DMF 1.885 g of a 60% suspension of NaH in mineral oil were added in an argon atmosphere. The mixture was stirred for 15 min at RT. 11.76 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 2 h at RT. After concentration in vacuo the residue was purified by chromatography on silica gel using CH2Cl2/ethylacetate=8/2. The fractions containing the product were evaporated. Yield: 16.05 g.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Clc1c(CBr)nc2ccccn12
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2nc3ccccn3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine (1.07 g, 5.87 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.539 g, 3.82 mmol) in anhydrous ethanol (30 mL) at 0° C. was added triethylamine (2.08 g, 2.86 mL, 20.57 mmol), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, and water was added to precipitate the product. The crude product was purified by column chromatography using dichloromethane and methanol (0-10%) to provide 2-[({3-chloroimidazo[1,2-a]pyridin-2-yl}methyl)sulfanyl]-6-methylpyrimidin-4-ol; 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 4.52 (s, 2H), 6.03 (bs, 1H), 7.07 (t, 1H), 7.35 (t, 1H), 7.59 (d, 1H), 8.30 (d, 1H); M+1 279.3.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C:31]12[O:42][CH2:41][CH2:40][CH2:39][O:38]1)(=[O:27])=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47]>O>[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47])[C:32](=[O:37])[C:31]12[O:38][CH2:39][CH2:40][CH2:41][O:42]1)(=[O:26])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)cc2C12OCCCO2
Reactant: CC(C)(C#N)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)ccc21
Temperature: 132 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of potassium t-butoxide (3.58 g, 31.9 mmol, 1.2 eq) in anhyd DMSO (72 mL) was added 5′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (12.20 g, 26.6 mmol ) all at one time under a dry N2 atmosphere. After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (9.38 g, 79.8 mmol, 3 eq) was added drop-wise and the reaction was heated at 132° C. for 21 hr. After cooling in an ice bath, the reaction mixture was poured into H2O and extracted with Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of CH2Cl2/CH3OH/NH4OH (99.25/0.5/0.25 to 96/2/1) to give the title compound as a yellow solid (9.48 g, 66% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[K+].[O:11]1[CH2:26][CH:12]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2>CO>[OH:11][CH:12]([CH2:26][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCC(O)CSc3ccccc3)ccc2N1
Reaction time: 8 h

Procedure:
4.11 gm (0.04 mol) of thiophenol were added to a suspension of 2.10 gm (0.03 mol) of potassium methylate in 40 ml of methanol, whereby a clear solution was obtained. Then, 4.38 gm of 6-(2,3-epoxy-propoxy)-3,4-dihydro-carbostyril (m.p. 125°-128° C.) were added while stirring, which also dissolved, accompanied by slight generation of heat. After 5 minutes the separation of a white crystal slurry started. After standing overnight, the crystals were suction-filtered off and recrystallized from a little methanol. White crystals with a melting point of 148°-149° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:11][CH2:10]1.Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]=[N:35][OH:36])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:11][CH2:10]1
Reactant: NO
Reactant: O=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(C=NO)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 32 h
Yield: 85.5 %

Procedure:
A solution of the product of Example 80 (0.40 g, 0.80 mmol), hydroxylamine hydrochloride (0.16 g, 2.4 mmol) and sodium acetate (0.19 g, 2.4 mmol) in ethanol (60 ml) was heated at reflux for 16 hours and stirred at room temperature for 32 hours. The mixture was evaporated in vacuo and extracted with ethyl acetate (50 ml). The organic phase was washed with brine (sat. 40 ml), dried (magnesium sulfate) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with 20-28% ethyl acetate/isohexane to give the oxime (0.36 g, 87%). 1H NMR (DMSO, 360 MHz): 1.49 (2H, bt, J=12.3), 1.82 (2H, bd, J=14.0), 2.40 (2H, bt, J=13.8), 2.50-2.60 (2H, m), 3.64 (1H, bs), 7.08-7.20 (2H, m), 7.28-7.34 (1H, m), 7.37 (2H, d, J=8.3), 7.72 (2H, d, J=8.3), 8.24 (1H, s), 9.76 (0.5H, d, J=5.9), 11.74 (0.5H, s)
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](Cl)=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][OH:21])=[S:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C(=O)C>O>[OH:21][CH2:20][CH2:19][NH:18][C:16]1[S:17][C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c(NC(=S)NCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccccc1)c1ccc2sc(NCCO)nc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 6 parts of N-(5-benzoyl-2-chlorophenyl)N'-(2-hydroxyethyl)thiourea, 2.5 parts of sodium hydride dispersion 75% and 90 parts of N,N-dimethylacetamide is stirred and heated quickly to 130° C. The reaction mixture is cooled, water is added and the whole is allowed to stand overnight. The precipitated product is filtered off, washed with water and crystallized from ethanol, yielding 2.8 parts of {2-[(2-hydroxyethyl)amino]-5-benzothiazolyl}phenylmethanone; mp. 159° C.
Reaction SMILES: [CH3:1][O:2]C(=O)CCBr.[CH3:8][Si:9]([CH3:39])([CH3:38])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:37]=[CH:36][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH2:33][CH2:34]O)[N:28]=[CH:27]4)=[CH:21][CH:20]=2)=[CH:17][CH:16]=[N:15]1>>[CH3:39][Si:9]([CH3:38])([CH3:8])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([CH2:33][CH2:34][CH2:1][OH:2])[N:28]=[CH:27]4)=[CH:36][CH:37]=2)=[CH:17][CH:16]=[N:15]1
Reactant: COC(=O)CCBr
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCO)c2)cc1
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCCO)c2)cc1

Procedure:
The titled compound AA is synthesized from intermediate Y-1 and 3-bromo-propionic acid methyl ester according to the procedure described for the synthesis of intermediate Y.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a mixture of 4-bromoindole (1 g, 5 mmol), and 2-biphenylboronic acid (1 g, 5 mmol) in THF (17 mL) were added Palladium catalyst Pd(PPh3)4 (0.2 g, 0. 17 mmol) and the freshly prepared sodium hydroxide solution (0.6 g, 15 mmol in 7 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 1.26 g (93%) of 4-biphenyl-2-yl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[NH:76][NH:75][C:74](=[O:77])[N:73]=2)=[CH:68][CH:67]=1>CN(C=O)C>[O:77]=[C:74]1[NH:75][NH:76][C:72]([C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:30])=[CH:67][CH:68]=2)=[N:73]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(-c2nc(=O)[nH][nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nc(=O)[nH][nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (264 mg, 0.56 mmol) in DMF (5 mL), HATU (Aldrich, 213 mg, 0.56 mmol) was added followed by the addition of DIPEA (0.1 mL) and 5-(4-amino-phenyl)-1,2-dihydro-[1,2,4]triazol-3-one (made above, 100 mg, 0.56 mmol). The mixture was stirred at rt for 4 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5% MeOH/methylene chloride) to give a white solid. 47 mg.
Reaction SMILES: [NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1.Cl>C(OCC)C>[NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:10]=[CH:9][CH:2]=[CH:3][CH:4]=1)=[O:5]
Reactant: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: NC(/C=C(\CCCC(=O)OCc1ccccc1)CP(=O)(O)O)CC(=O)OCc1ccccc1

Procedure:
To a suspension of 3.0 g (9.3 mmol) of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate in 19.1 ml (185.6 mmol) of benzyl alcohol are added 40 ml of a 4N solution of hydrochloric acid in diethyl ether. The solution formed is allowed to stand for 1 week. The reaction mixture is evaporated to dryness. The residue is dissolved in 35 ml of ethanol, and a solution of 35 ml of propylene oxide in 35 ml of ethanol is added. The crystalline precipitate formed is collected, re-crystallized twice from water and dried over phosphorus pentoxide, affording dibenzyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate of m.p. 220°-221° (decomp).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20](I)=[CH:19][C:15]4[CH2:16][CH2:17][O:18][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:22])[N:3]=1.C(O)(C(F)(F)F)=O.C1C(=O)[N:34](I)C(=O)C1>C(#N)C>[O:18]1[C:14]2[CH:13]=[C:12]([CH2:11][C:7]3[NH:8][C:9]4[C:5]([N:6]=3)=[C:4]([NH2:22])[N:3]=[C:2]([NH2:34])[N:10]=4)[CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17]1
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)CCO4)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N)c2nc(Cc3ccc4c(c3)OCC4)[nH]c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin-6-amine (S16-9). To a suspension of S16-8 (0.45 g, 1.6 mmol) in 50 mL acetonitrile was added 1 mL of TFA. To the resulting solution was added NIS (1.06 g, 4.7 mmol) and the reaction mixture was stirred at rt for 3 h. It was then evaporated to dryness and purified by flash chromatography to give S16-9 (0.408 g, 63%) as a yellow solid. 1H NMR (500 MHz, MeOH-d4) δ 7.67 (s, 1H), 6.76 (s, 1H), 4.59 (m, 2H), 4.28 (s, 2H), 3.21 (m, 2H); MS: m/z 412 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]3[N:9]([C:13]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:37]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:8]3[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:11]=[CH:10][N:9]3[C:13]=2[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:24]=2)=[CH:21][CH:20]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2nc3c(NC4CCCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
To a solution of 4-{8-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}phenol (110 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (27 μL, 0.31 mmol) and cesium carbonate (160 mg, 0.48 mmol). The mixture was heated at 80° C. for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-8-amine (40 mg, 34%) as a yellow foam. 1H NMR (CDCl3): δ 8.87 (d, 1H), 8.04 (d, 1H), 7.57 (d, 2H), 6.95 (d, 2H), 6.75 (t, 1H), 6.40 (d, 1H), 6.26 (d, 1H), 6.1 (m, 1H), 5.43 (d, 1H), 5.30 (m, 3H), 4.58 (d, 2H), 4.35 (m, 1H), 3.92 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Br)=[CH2:11]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]=[CH2:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 4-fluorobenzaldehyde (8.5 g, 68.2 mmol, Aldrich) in 50 mL of tetrahydrofuran was added dropwise to a solution of vinylmagnesium bromide (9.84 g, 75 mmol, Aldrich) in 150 mL of tetrahydrofuran at 0° C. The mixture was stirred for min and then allowed to warm to room temperature. The reaction was stirred overnight and quenched by the addition of water (100 mL). The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo and then dissolved in 200 mL of ethyl acetate. This solution was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to 10.3 g of an amber oil as product. NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.04 (dd, 2H, J=9 Hz, 9 Hz), 6.08-5.97 (m, 1H), 5.35 (d, 1H, J=17 Hz), 5.21 (d, 2H, J=10 Hz), 1.90 (d, 1H, J=4 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[C:7]([CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][C:7]=1[CH:20]([OH:26])[C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23]
Reactant: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(C)C(O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 21.4 (530 mg, 1479 μmol) in THF (20 mL), was added LAH (168 mg, 4436 μmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was then removed, and the residue was diluted with EtOAc. The organic layer was washed with 1N NaOH, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and the organic solvent was removed in vacuo to give an oil (442 mg, 90%) which was used without further purification. MS ESI m/e: 331.2 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:28])[CH:8]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:9]1[C:17]2[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=O)=O.Br[C:30]1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCC#N)=C[N:34]=1>CS(C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:7]([CH3:28])[CH2:6][C:30]#[N:34])=[CH:22][CH:23]=1
Reactant: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C(C)COS(C)(=O)=O)c[nH]c12
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C(C)CC#N)c[nH]c12

Procedure:
The title compound was prepared starting from 215 mg (0.49 mmol) of the compound from Example 71A in analogy to the synthesis of the compound from Example 53, but with dimethyl sulfoxide as solvent. 177 mg (98% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]2[C:19]3[C:20]([CH3:32])=[C:21]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]=3[O:17][C:16]2([CH3:34])[CH3:33])=[CH:11][CH:10]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]4[O:17][C:16]([CH3:34])([CH3:33])[CH:15]([C:12]5[CH:13]=[N:14][C:9]([F:8])=[CH:10][CH:11]=5)[C:19]=4[C:20]=3[CH3:32])[CH2:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Yield: 50 %

Procedure:
Using fluorobenzene and 1-(3-(6-fluoropyridine-3-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 127, the title compound was obtained in the same manner as in Example 16. Yield 50%. Amorphous powder.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=2)[C:10](=[O:17])[CH2:9][CH2:8]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
To 1.7 mL (3.0 g, 30.6 mmol, 18M) H2SO4 at -5;C (ice-NaCl bath) was slowly added 783.0 mg (4.49 mmol) of 3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO3 (426.7 mg 6.88 mmol, 0.43 mL, 16 , and 1.31 g (0.013 mol, 0.74 mL, 18 M) of H2SO4 were slowly added. After 20 min, ice was added and the resulting mixture was extracted with EtOAc. The combined extracts were concentrated under reduced pressure to give a yellow oil from which the title compound, a pale yellow solid, was isolated by column chromatography (10% EtOAC/hexanes).